Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
A Study of LY4101174 in Participants With Recurrent, Advanced or Metastatic Solid Tumors
The purpose of this study is to find out whether the study drug, LY4101174, is safe, tolerable and effective in participants with advanced, or metastatic solid tumors. The study is conducted in two parts - phase Ia (dose-escalation, dose-optimization) and phase Ib (dose-expansion). The study will last up to approximately 4 years.
* Have one of the following solid tumor cancers:
* Cohort A1: urothelial carcinoma, triple negative breast cancer, non-small cell lung cancer, esophageal cancer, pancreatic cancer, ovarian cancer, cervical cancer (squamous cell carcinoma), head and neck squamous cell carcinoma or prostate cancer
* Cohort A2/B1/B2: urothelial carcinoma
* Cohort C1: triple negative breast cancer
* Cohort C2: non-small cell lung cancer
* Cohort C3: ovarian or fallopian tube cancer
* Cohort C4: cervical cancer
* Cohort C5: head and neck squamous cell carcinoma
* Prior Systemic Therapy Criteria:
* Cohort A1/C1-5: Individual has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating investigator; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies
* Cohort A2/B1/B2: Individual must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
* Prior enfortumab vedotin specific requirements:
* Cohorts A1/A2/C1-5: prior treatment with enfortumab vedotin is allowed, but not required
* Cohort B1: individual must be enfortumab vedotin naive in the advanced/metastatic setting
* Cohort B2: individual must have received enfortumab vedotin in the metastatic/advanced setting.
* Measurability of disease
* Cohort A1: measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1)
* Cohorts A2, B1, B2, C1-5: measurable disease required as defined by RECIST v1.1
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country specific regulations
Exclusion Criteria:
* Individual with known or suspected uncontrolled CNS metastases
* Individual with uncontrolled hypercalcemia
* Individual with uncontrolled diabetes
* Individual with evidence of corneal keratopathy or history of corneal transplant
* Any serious unresolved toxicities from prior therapy
* Significant cardiovascular disease
* Current of history of intestinal obstruction in the previous 3 months
* Recent thromboembolic event or bleeding disorder
* Prolongation of QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms
* History of pneumonitis/interstitial lung disease
* History of Grade ≥3 skin toxicity when receiving enfortumab vedotin
* Individuals who are pregnant, breastfeeding or plan to breastfeed during study or within 30 days of last dose of study intervention
DRUG: LY4101174
Prostate Cancer, Esophageal Cancer, Non-Small Cell Lung Cancer, Pancreatic Cancer, Bladder Cancer, Ovarian Cancer, Cervical Cancer, Head and Neck Squamous Cell Carcinoma, Triple Negative Breast Cancer, Advanced Solid Tumor, Breast - Female, Breast - Male, Cervix, Esophagus, Larynx, Lip, Oral Cavity and Pharynx, Lung/Thoracic, Ovary, Pancreas, Prostate, Urinary Bladder, Metastatic Solid Tumor, Recurrent Solid Tumor, Urinary Bladder Neoplasm, Renal Pelvis Cancer
A Safety and Efficacy Study of HCB101, Fc-fusion Protein Targeting SIRPα-CD47 Pathway, in Solid or Hematological Tumors
The purpose of this study is to find out whether IV injection of HCB101 is an effective
treatment for different types of advanced solid tumors or relapsed and refractory non-Hodgkin
lymphoma and what side effects (unwanted effects) may occur in subjects aged 18 years old and
above.
• Able to understand and willing to sign the ICF.
• Male and female subjects of ≥18 years of age.
• Histologically/cytologically confirmed, locally advanced solid tumor: subjects with
histologically or cytologically confirmed advanced solid tumors refractory to standard
therapy, or for which no standard treatment exists or non-Hodgkin lymphoma, relapsed
or refractory to at least 2 prior lines of therapy.
• For subjects with advanced solid tumor - must have at least 1 measurable lesion as
defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at baseline.
• For subjects with non-Hodgkin lymphoma - must have non-Hodgkin lymphoma that is
measurable or assessable for response per Lugano Classification (with 2016
refinement).
• Must have ECOG performance status of 0 to 2 at Screening.
• Able to provide tumor tissue samples.
• Have life expectancy of ≥12 weeks.
Exclusion Criteria:
• With known history of hypersensitivity to any components of HCB101.
• Known active or untreated CNS metastases and/or carcinomatous meningitis.
• Have undergone a major surgery or radical radiotherapy or palliative radiotherapy or
have used a radioactive drug that is not completed at least 2 weeks prior to the first
dose of HCB101.
• Clinically significant cardiovascular condition.
• Any previous treatment-related toxicities which have not recovered to ≤ Grade 1 as
evaluated by National Cancer Institute, Common Terminology Criteria for Adverse Events
(NCI CTCAE) version 5.0 or baseline, except alopecia and anemia.
• With known inherited or acquired bleeding disorder or bleeding diathesis. .
• Have RBC transfusion within 4 weeks prior to Screening.
• With a previously documented diagnosis of hemolytic anemia or Evans Syndrome in the
last 3 months.
• Any investigational or approved systemic cancer therapy.
• Active use of vitamin K antagonist anticoagulant like warfarin. Use of low molecular
weight heparin and factor Xa inhibitors will be permitted on case by case basis. There
will be no restriction for daily aspirin ≤ 81 mg/QD.
• Have used herbal medication within 14 days prior to the first dose of HCB101.
• Have received any treatment targeting the CD47 or SIRPα pathway.
• Have other malignancies requiring treatment within 2 years prior to the first dose of
HCB101.
• Participation in another clinical study with an investigational product administered
in the last 14 days prior to receiving the first dose of HCB101.
• An investigational device used within 28 days prior to the first dose of HCB101.
• Positive for hepatitis B, active hepatitis C infections, positive for HIV, or known
active or latent tuberculosis.
• Known to have a history of alcoholism or drug abuse.
Drug: HCB101
Multiple Myeloma, Advanced Solid Tumor, Refractory Non-Hodgkin Lymphoma, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Kaposis sarcoma, Non-Hodgkins Lymphoma, Small Intestine
Immunotherapy, CD47, SIRPα, Solid Tumor, Lymphoma
UT Southwestern; Parkland Health & Hospital System
A Study of LOXO-435 in Participants With Cancer With a Change in a Gene Called FGFR3
The main purpose of this study is to learn more about the safety, side effects, and effectiveness of LOXO-435. LOXO-435 may be used to treat cancer of the cells that line the urinary system and other solid tumor cancers that have a change in a particular gene (known as the FGFR3 gene). Participation could last up to 30 months (2.5 years) and possibly longer if the disease does not get worse.
* Have solid tumor cancer with an FGFR3 pathway alteration on molecular testing in tumor or blood sample that is deemed as actionable.
* Cohort A1 (Dose Escalation): Presence of an alteration in FGFR3 or its ligands.
* Cohort A2 (Dose Optimization): Histological diagnosis of urothelial cancer (UC) that is locally advanced or metastatic with a qualifying FGFR3 alteration.
* Cohorts B1, B2 and B3 (Dose Expansion): Histological diagnosis of urothelial cancer that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
* Cohort C (Dose Expansion): Must have histological diagnosis of a non-urothelial solid tumor malignancy that is locally advanced or metastatic with a prespecified activating FGFR3 alteration.
* Measurability of disease:
* Cohort A1: Measurable or non-measurable disease as defined by Response Evaluation Criteria in Solid Tumors v 1.1 (RECIST v1.1)
* Cohorts A2, B1, B2, B3, and C1: Measurable disease required as defined by RECIST v1.1
* Have adequate archival tumor tissue sample available or undergo a screening biopsy if allowed per country-specific regulations.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Prior Systemic Therapy Criteria:
* Cohort A1/C1: Participant has received all standard therapies for which the participant was deemed to be an appropriate candidate by the treating Investigator; OR the participant is refusing the remaining most appropriate standard of care treatment; OR there is no standard therapy available for the disease. There is no restriction on number of prior therapies.
* Cohort A2/B1/B2/B3: Participants must have received at least one prior regimen in the advanced or metastatic setting. There is no restriction on number of prior therapies.
* FGFR inhibitor specific requirements:
* Cohort A1/A2: Prior FGFR inhibitor treatment is permitted, but not required.
* Cohort B1: Participants must have been previously treated with a FGFR inhibitor.
* Cohort B2, B3, C1: Participants must be FGFR inhibitor naïve.
Exclusion Criteria:
* Participants with primary central nervous system (CNS) malignancy.
* Known or suspected history of uncontrolled CNS metastases.
* Current evidence of corneal keratopathy or retinal disorder.
* Have a history and/or current evidence of extensive tissue calcification.
* Any serious unresolved toxicities from prior therapy.
* Significant cardiovascular disease.
* Prolongation of the QT interval corrected for heart rate using Fridericia's formula (QTcF).
* Active uncontrolled systemic infection or other clinically significant medical conditions.
* Participants who are pregnant, lactating, or plan to breastfeed during the study or within 6 months of the last dose of study treatment. Participants who have stopped breastfeeding may be enrolled.
DRUG: LOXO-435, DRUG: Pembrolizumab
Neoplasm Metastasis, Urinary Bladder Neoplasms, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Urinary Bladder, Kaposis sarcoma, Small Intestine, Soft Tissue, Unknown Sites, Ureteral Neoplasms
A Safety, Tolerability and Efficacy Study of NC410 Plus Pembrolizumab in Participants With Advanced Unresectable or Metastatic Solid Tumors
This is an open-label, non-randomized, Phase 1b/2 study to determine the safety and tolerability of NC410 when combined with a standard dose of pembrolizumab. This study will also assess the clinical benefit of combination therapy in participants with advanced unresectable and/or metastatic ICI refractory solid tumors OR ICI naïve MSS/MSI-low solid tumors
* Be 18 years of age on day of signing informed consent.
* Participant with histologically or cytologically confirmed diagnosis of the following advanced unresectable and/or metastatic solid tumors:
* Phase 1b: Participants with solid tumors that are known to be associated as MSS/MSI-low in the majority including: CRC (without liver metastasis), Gastric including GE junction, Esophageal, Ovarian, and H\&N cancer (regardless of prior treatment with ICIs). Note: Participants must have had disease progression after at least one line of systemic standard of care therapy prior to enrollment. Participants who discontinue standard treatment due to intolerance or refuse standard treatment will also be eligible to enroll.
* Phase 2 ICI Refractory Solid Tumors (Cohort 1): Participants with solid tumors including CRC, Gastric including GE junction, Esophageal, Endometrial, H\&N, Lung, Cervical and Ovarian cancer.Participants must have progressed on treatment with an anti-PD1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
* Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
* Has demonstrated disease progression after PD-1/L1 as defined by RECIST v1.1.
* Phase 2 ICI naïve Solid Tumors (Cohorts 2a-2c):Tumors known to be associated with MSS/MSI-low status such as CRC, Gastric including GE junction, and Ovarian cancer where participants have not been previously treated with ICIs. Note: Participants must have had disease progression after at least one line of systemic standard of care therapy prior to enrollment. Participants who discontinue standard treatment due to intolerance or refuse standard treatment will also be eligible to enroll. Note: Confirmation of MSS/MSI status should be assessed prior to study entry (either by historical result or during screening).
* A male participant must agree to use contraception and refrain from sperm donation or expecting to father a child, from Screening through the treatment period and for at least 120 days after the last dose of study treatment.
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
* Not a woman of childbearing potential (WOCBP)
* A WOCBP who agrees to follow contraceptive guidance outlined in the protocol from Screening through the treatment period and for at least 120 days after the last dose of study treatment.
* Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Able to provide tumor tissue sample at Screening, archival (≤ 5 years old) or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
* Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
* Life expectancy greater than or equal to 12 weeks as judged by the Investigator.
* Have adequate organ function as defined in the protocol.
Exclusion Criteria:
* A WOCBP who has a positive urine pregnancy test (within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137), and was discontinued from that treatment due to a Grade 3 or higher irAE.
* Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-life drugs) prior to treatment. Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy may be eligible. Participants with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement may be eligible. If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
* Has received prior radiotherapy within 2 weeks of start of study treatment or has had a history of radiation pneumonitis. Note: Participants must have recovered from all radiation-related toxicities and do not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
* Has received G-CSF or GM-CSF within 7 days prior to start of study treatment.
* Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
* Receipt of COVID-19 vaccine within ≤ 14 days prior to first administration of study treatments. For 2-dose COVID-19 vaccines or COVID-19 booster, participants must wait at least 14-days after administration prior to beginning study treatment.
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
* Has had an allogeneic tissue/stem cell/solid organ transplant.
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
* Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, that have undergone potentially curative therapy are not excluded.
* Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
* Has severe hypersensitivity (≥ Grade 3), known allergy or reaction to Pembrolizumab, NC410, and/or any of their excipients.
* Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
* Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
* Has an active infection requiring systemic therapy.
* Has a known active or history of HIV infection. No HIV testing is required unless mandated by local health authority.
* Has known active Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
* Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
DRUG: NC410, DRUG: pembrolizumab
Lung Cancer, Endometrial Cancer, Esophageal Cancer, Gastric Cancer, Ovarian Cancer, Cervical Cancer, Advanced or Metastatic Solid Tumors, Colon, Lung/Thoracic, Other Female Genital, Other Male Genital, Ovary, Pancreas, Microsatellite Instability Low, Microsatellite Instability High, Microsatellite Stable, Colo-rectal Cancer, Head Neck Cancer
A Study of ASP2138 Given by Itself or Given With Other Cancer Treatments in Adults With Stomach Cancer, Gastroesophageal Junction Cancer, or Pancreatic Cancer
Claudin 18.2 protein, or CLDN18.2 is a protein found on cells in the digestive system. It is also found on some tumors. Researchers are looking at ways to attack CLDN18.2 to help control tumors. ASP2138 is thought to bind to CLDN18.2 and a protein called on a type of immune cell called a T-cell. This "tells" the immune system to attack the tumor.
ASP2138 is a potential treatment for people with stomach cancer, gastroesophageal junction cancer, (GEJ cancer) or pancreatic cancer. GEJ is where the tube that carries food (esophagus) joins the stomach). Before ASP2138 is available as a treatment, the researchers need to understand how it is processed by and acts upon the body. In this study, ASP2138 will either be given by itself, or given together with standard treatments for gastric, GEJ and pancreatic cancer. Pembrolizumab and mFOLFOX6 (modified leucovorin \[folinic acid\], 5-FU \[fluorouracil\], and oxaliplatin), and ramucirumab and paclitaxel are standard treatments for gastric and GEJ cancer. mFOLFIRINOX (modified leucovorin \[folinic acid\], 5-FU \[fluorouracil\], irinotecan and oxaliplatin) is a standard treatment for pancreatic cancer. This information will help to find a suitable dose of ASP2138 given by itself and together with the standard cancer treatments and to check for potential medical problems from the treatments.
Adults 18 years or older with stomach cancer, GEJ cancer, or pancreatic cancer can take part. Their cancer is locally advanced unresectable or metastatic. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body.
The main aims of the study are to check the safety of ASP2138, and how well people cope with (tolerate) any medical problems during the study, and to find a suitable dose of ASP2138 to be used later in this study. These are done for ASP2138 given by itself and when given together with the standard cancer treatments.
The study will have 2 phases. In phase 1, different small groups of people will receive lower to higher doses of ASP2138 given by itself or together with the standard cancer treatments. Any medical problems will be recorded at each dose. This is done to find suitable doses of ASP2138 to use later in the study. Doctors will also check how each type of cancer responds to ASP2138. In phase 1b, other different small groups will receive suitable doses of ASP2138 given by itself or together with the standard cancer treatments. Suitable doses will be found from phase 1. Phase 1b will check how each type of cancer responds to ASP2138 given by itself or together with the standard cancer treatments. The response to ASP2138 is measured using scans and blood tests. Safety checks will be done at each visit and the doctors will continue to check for all medical problems throughout the study.
ASP2138 will be given either through a vein (intravenous infusion) or just below the skin (subcutaneous injection). Treatment will be in a 14-day cycle (2 weeks). In each treatment cycle, intravenous infusions or subcutaneous injections will either be given once a week or once every 2 weeks.
People will continue to receive treatment until their cancer gets worse or the doctor decides to stop the person's treatment. People will visit the clinic on certain days during their treatment, with extra visits during the first 3 cycles of treatment.
After treatment has finished, people will visit the clinic for a health check several times. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their treatment or not.
* Participant is considered an adult according to local regulation at the time of signing the informed consent form (ICF).
* Female participant is not pregnant, confirmed by serum pregnancy test and medical evaluation by interview and at least 1 of the following conditions apply:
* Not a woman of childbearing potential (WOCBP)
* WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 6 months after final study intervention administration.
* Female participant must agree not to breastfeed starting at screening and throughout the study period and for 6 months after the final study intervention administration.
* Female participant must not donate ova starting at screening and throughout the study period and for 6 months after the final study intervention administration.
* Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 6 months after the final study intervention administration.
* Male participant must not donate sperm during the treatment period and for 6 months after the final study intervention administration.
* Male participant with pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study intervention administration.
* Participant's tumor sample is positive for claudin (CLDN)18.2 expression by central immunohistochemistry (IHC) testing.
* Participant has radiographically-confirmed, locally advanced, unresectable or metastatic disease within 28 days prior to the first dose of study intervention.
* Participant has at least 1 measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to the first dose of study intervention. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
* Participant has QT interval by Fredericia (QTcF) =\< 470 msec.
* Participant agrees not to participate in another interventional study while receiving study Intervention in the present study.
* Participant has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Participant has predicted life expectancy \>= 12 weeks.
* Participant must meet all of criteria based on laboratory tests within 7 days prior to the first dose of study Intervention. In case of multiple laboratory data within this period, the most recent data should be used. If a participant has received a recent blood transfusion, the laboratory tests must be obtained \>= 2 weeks after any blood transfusion.
Monotherapy Disease specific Criteria: Gastric/GEJ Cancer
* Participant has histologically confirmed gastric/gastroesophageal junction (GEJ) adenocarcinoma.
* Escalation: Participant with gastric/GEJ adenocarcinoma who has progressed, is intolerant, has refused, or for whom there is no standard approved therapies that impart significant clinical benefit (no limit to the number of prior treatment regimens).
* Unique to South Korea: Participant with gastric/GEJ adenocarcinoma who has refused standard approved therapies is not allowed.
* Expansion: Participant with gastric/GEJ adenocarcinoma must have received no more than 3 prior lines of systemic chemotherapy treatment.
Monotherapy Disease specific Criteria: Pancreatic Cancer
* Participant has histologically or cytologically confirmed pancreatic adenocarcinoma.
* Escalation: Participant with pancreatic adenocarcinoma who has progressed, is intolerant, has refused, or for whom there is no standard approved therapies that impart significant clinical benefit (no limit to the number of prior treatment regimens).
* Unique to South Korea: Participant with pancreatic adenocarcinoma who has refused standard approved therapies is not allowed.
* Expansion: Participants with pancreatic adenocarcinoma must have received no more than 2 prior lines of systemic chemotherapy treatment.
For all participants in combination therapy administration:
* If a participant has received a recent blood transfusion, the laboratory tests must be obtained ≥ 1 week after any blood transfusion.
Combination Therapy Disease specific Criteria: ASP2138 in Combination with Pembrolizumab and mFOLFOX6 as First-line Therapy in Gastric/GEJ Cancer
* Participant has histologically confirmed diagnosis of gastric/GEJ adenocarcinoma.
* Participant has metastatic or locally advanced unresectable gastric/GEJ adenocarcinoma.
* Participant with gastric/GEJ adenocarcinoma has progressed and must not have been previously treated for metastatic disease with either chemotherapy or prior checkpoint inhibitor therapy.
* Participant has a human epidermal growth factor receptor 2 (HER2)-negative tumor per local testing.
Combination Therapy Disease Specific Criteria: ASP2138 in Combination with Ramucirumab and Paclitaxel as Second-line Therapy in Gastric/GEJ Cancer
* Participant has histologically confirmed diagnosis of gastric/GEJ adenocarcinoma.
* Participant has metastatic or locally advanced unresectable gastric/GEJ adenocarcinoma.
* Participant with gastric/GEJ adenocarcinoma must have previously received 1 line of systemic chemotherapy treatment (i.e., documented objective radiological or clinical disease progression during or within 4 months of the last dose of first line platinum and fluoropyrimidine doublet or disease progression during or after perioperative fluorouracil, leucovorin, oxaliplatin and docetaxel \[FLOT\]).
Combination Therapy Disease specific Criteria: ASP2138 in Combination with mFOLFIRINOX as First-line Therapy in Pancreatic Cancer
* Participant has histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma.
* Participant has confirmed metastatic or locally advanced unresectable pancreatic adenocarcinoma.
* Participant has pancreatic adenocarcinoma, has progressed and must not have received prior systemic anticancer therapy for their advanced disease.
Exclusion Criteria:
* Participant has received other investigational agents, or antineoplastic therapy including other immunotherapy or devices concurrently or within 21 days or 5 times the half-life, whichever is shorter, prior to first dose of study intervention administration.
* Participant has any condition which makes the participant unsuitable for study participation.
* Participant has known immediate or delayed hypersensitivity or contraindication to any component of study intervention.
* Participant has had prior severe allergic reaction or intolerance to known ingredients of ASP2138 or other antibodies, including humanized or chimeric antibodies.
* Participant weighs \< 40 kg.
* Participant has received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to first dose of study intervention. Participant using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single daily dose of systemic corticosteroids or receiving systemic corticosteroids as pre-medication for radiologic imaging contrast use are allowed.
* Participant has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
* Participant has significant gastric bleeding and/or untreated gastric ulcers that exclude the participant from participation.
* Participant has symptomatic CNS metastases or participant has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Participants with previously treated CNS metastases are eligible, if they are clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study intervention and are not requiring immunosuppressive doses of systemic steroids (\> 30 mg per day of hydrocortisone or \> 10 mg per day of prednisone or equivalent) for longer than 2 weeks.
* Participant is known to have HIV infection. However, participants with cluster of differentiation (CD4) + T cell counts \>= 350 cells/µL and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the past 6 months are eligible. NOTE: Screening for human immunodeficiency virus (HIV) infection should be conducted per local requirements.
* Participant is known to have active hepatitis B (positive hepatitis B surface antigen \[HBsAg\]) or hepatitis C infection. Testing is required for known history of these infections or as mandated by local requirements. NOTE: Screening for these infections should be conducted per local requirements.
* For participant who is negative for HBsAg, but hepatitis B core antibody (HBc Ab) positive, a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test will be performed and if positive the participant will be excluded.
* Participant with positive hepatitis C virus (HCV) serology, but negative HCV ribonucleic acid (RNA) test results are eligible.
* Participant treated for HCV with undetectable viral load results are eligible
* Participant has had within 6 months prior to first dose of study intervention any of the following: unstable angina, myocardial infarction, ventricular arrhythmia requiring intervention or hospitalization for heart failure.
* Participant has active infection requiring systemic therapy that has not completely resolved within 7 days prior to the start of study intervention.
* Participant has active autoimmune disease that has required systemic immunosuppressive treatment within the past 1 month prior to the start of study intervention.
* Participant has a clinically significant disease or co-morbidity that may adversely affect the safe delivery of treatment within this study or make the participant unsuitable for study participation.
* Participant has psychiatric illness or social situations that would preclude study compliance.
* Participant has had a major surgical procedure 28 days before start of study intervention and has not fully recovered.
* Participant has received radiotherapy metastatic or for locally advanced unresectable gastric/GEJ or metastatic pancreatic adenocarcinoma 14 days prior to start of study intervention and has NOT recovered from any related toxicity.
* Participant has another malignancy for which treatment is required.
* Participant who has received CLDN18.2-targeted therapy (e.g., zolbetuximab or chimeric antigen receptor CLDN18.2-specific T cells) prior to first dose of study intervention administration is not eligible for dose escalation cohorts. However, a participant who has received CLDN18.2-targeted therapy greater than 28 days or 5 half-lives (whichever is longer) prior to first dose study intervention administration is eligible for dose expansion cohorts only, with the exception of participants who have experienced Grade \>= 3 gastrointestinal toxicity after receiving an CLDN18.2-targeted therapy.
* Participant has a history or complication of interstitial lung disease.
China Specific:
Participant who has received treatment with herbal medications that have known antitumor activity within 28 days prior to first dose of study treatment.
For all participants in combination therapy administration:
* Participant has prior severe allergic reaction; suspected, known immediate or delayed hypersensitivity; or intolerance or contraindication to any study intervention (i.e., pembrolizumab and mFOLFOX6 \[all components\], ramucirumab and paclitaxel or mFOLFIRINOX \[all components\]).
* For 5 FU (fluorouracil): Participant has known dihydropyrimidine dehydrogenase (DPD) deficiency. (NOTE: Screening for DPD deficiency should be conducted per local requirements).
* Participants who have received systemic immunosuppressive therapy, including systemic corticosteroids 14 days prior to the first dose of study intervention are generally excluded; however, participants using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single daily dose of systemic corticosteroids or receiving systemic corticosteroids as pre-medication for radiologic imaging contrast or for chemotherapy (as part of combination therapy administration) are allowed.
* Participant is known to have HIV infection.
* NOTE: Differing from monotherapy administration, participants with CD4+ T cell counts ≥ 350 cells/µL and no history of AIDS-defining opportunistic infections within the past 6 months remain ineligible.
* NOTE: Screening for HIV infection should be conducted per local requirements.
* Participant has had uncontrolled high blood pressure within 6 months prior to the first dose of study intervention.
* Participant has a history of ascites requiring drainage more than twice in the past 7 days.
Study of GS-1811 Given Alone or With Zimberelimab in Adults With Advanced Solid Tumors
This is a first-in-human (FIH) study to evaluate the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of GS-1811 as monotherapy and in combination with zimberelimab in participants with advanced solid tumors.
This study will be conducted in 6 parts (Parts A, B, and E: monotherapy, Parts C and D: combination therapy, and Part F for both monotherapy and combination therapy) in participants with advanced solid tumors who have received, been intolerant to, or been ineligible for all treatments known to confer clinical benefit or in participants with select solid tumors.
* Disease:
* Part A: Individuals with histologically or cytologically confirmed advanced solid tumors who have received, been intolerant to, or been ineligible for all treatment known to confer clinical benefit.
* Part B: Individuals with histologically or cytologically confirmed select indications who have received, been intolerant to, or been ineligible for all treatment known to confer clinical benefit.
* Part C: Individuals with histologically or cytologically confirmed advanced solid tumors who have received, been intolerant to, or been ineligible for all treatments known to confer clinical benefit or whose disease is indicated for anti- programmed cell death protein 1 or programmed cell death ligand 1 (PD-\[L\]1) monoclonal antibody monotherapy.
* Part D: Individuals with pathologically confirmed select advanced solid tumors.
* Part E: Individuals with pathologically confirmed select advanced solid tumors. Participants must have received, have been intolerant to, or have been ineligible for all treatment known to confer clinical benefit.
* Part F: Individuals with pathologically-confirmed select advanced solid tumors. Participants must have received, have been intolerant to, or have been ineligible for all treatments known to confer clinical benefit; or, for participants who will undergo combination therapy, have disease which is indicated for anti-PD-(L)1 mAb monotherapy.
* Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 for individuals in Parts A, B, and C, and 0 or 1 for individuals in Parts D, E, and F.
* Adequate organ function.
* Male individuals and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use methods of contraception.
* Tissue requirement:
* Parts A, C, D, E and F: Must provide pre-treatment adequate tumor tissue sample prior to enrollment.
* Part B and select participants in Parts C and F: Must have fresh pre-treatment and on-treatment biopsies for biomarker analysis.
Key
Exclusion Criteria:
* Concurrent anticancer treatment.
* Any anti-cancer therapy, whether investigational or approved, within protocol specified time prior to initiation of study including: immunotherapy or biologic therapy (\< 28 days), chemotherapy (\< 21 days), targeted small molecule therapy (\< 14 days), hormonal therapy or other adjunctive therapy (\< 14 days) or radiotherapy (\< 21 days).
* Any prior CCR8 directed therapy.
* Prior allogeneic tissue/solid organ transplantation, including allogeneic stem cell transplantation. Exception: prior corneal transplant without requirement for systemic immunosuppressive agents is allowed.
* Concurrent active malignancy other than nonmelanoma skin cancer, curatively resected carcinoma in situ, localized prostate cancer, or superficial bladder cancer after undergoing potentially curative therapy with no evidence of disease. Individuals with other previous malignancies are eligible if disease-free for \> 2 years.
* History of intolerance, hypersensitivity, or treatment discontinuation due to severe immune-related adverse events (irAEs) on prior immunotherapy.
* History of autoimmune disease or active autoimmune disease requiring systemic treatment within 2 years.
* History of pneumonitis, interstitial lung disease, or severe radiation pneumonitis (excluding localized radiation pneumonitis).
* Active and clinically relevant bacterial, fungal, or viral infection that is not controlled or requires IV antibiotics.
* Active hepatitis B virus (HBV) and/or hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV).
* Positive serum pregnancy test or breastfeeding female.
* Live vaccines within 30 days prior to first dose.
* Significant cardiovascular disease.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Olanzapine Versus Megestrol Acetate for the Treatment of Loss of Appetite Among Advanced Cancer Patients
This phase III trial compares the effects of olanzapine versus megestrol acetate in treating loss of appetite in patients with cancer that has spread to other places in the body (advanced). Olanzapine may stimulate and increase appetite. This study aims to find out if olanzapine is better than the usual approach (megestrol acetate) for stimulating appetite and preventing weight loss.
* Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
* Diagnosis of advanced cancer
* Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or physician-estimated caloric intake of less than 20 calories/kilogram of body weight per day
* The patient must perceive loss of appetite and/or weight as a problem; and have an appetite score of 4 or worse on the "Please rate your appetite...." question that requires a patient response on a 0-10 numeric rating scale
* Not receiving ongoing tube feedings or parenteral nutrition at the time of registration
* Not currently using systemic adrenal steroids (with the exception of short-term dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
* No use of androgens, progesterone analogs, or other appetite stimulants within the past month
* Patient should not have poorly controlled hypertension or congestive heart failure at registration
* Patient should not have an obstruction of the alimentary canal, malabsorption, or intractable vomiting (defined as vomiting more than 3 times per day over the preceding week)
* Not currently using olanzapine for another medical condition or had previously used olanzapine for chronic nausea or for any pre-existing psychotic disorder
* Patient should not have had a previous blood clot at any time in the past
* No history of poorly controlled diabetes
* No symptomatic leptomeningeal disease or known brain metastases as these patients may have difficulty taking oral medications
* No history of hypersensitivity to olanzapine or megestrol acetate
* No COVID-19 infection in the past that, in the opinion of the treating physician, had left patients with compromised taste, which has not resolved at the time of registration
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =\< 14 days prior to registration is required
* Age \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
* Estimated life expectancy of 3 months or longer
* Serum creatinine =\< 2.0 mg/dL
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 3 x upper limit of normal (ULN)
* Fasting glucose \< 140 mg/dL
* Granulocytes \> 1000/hpf
* No treatment with another antipsychotic agent, such as risperidone, quetiapine, clozapine, butyrophenone within 30 days of enrollment
* In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking patients should have access to Spanish speaking staff on site or through the use of a translation service to be able to conduct the informed consent discussion in Spanish, and to conduct the weekly phone calls
Exclusion Criteria:
* Psychiatric illness which would prevent the patient from giving informed consent
* Medical condition such as uncontrolled infection (including human immunodeficiency virus \[HIV\]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
* Patients who cannot swallow oral formulations of the agents
* Patients with impaired decision-making capacity (such as with a diagnosis of dementia or memory loss) are not eligible for this study
* No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate cancer (this exclusion criterion is intended to circumvent any confounding antineoplastic effects of megestrol acetate)
Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Patients With Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial
The dose escalation phase of this trial identifies the safety, side effects and best dose of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Ceralasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene.
* DOSE-ESCALATION PHASE: Must have histologically confirmed advanced solid tumor including but not restricted to breast cancer, gastric or gastroesophageal cancer, colon cancer, endometrial cancer, salivary gland tumors, and hepatobiliary tumors
* DOSE-EXPANSION PHASE: Must have histologically confirmed advanced/metastatic gastroesophageal cancer (cohort A) or colorectal cancer (cohort B)
* DOSE-EXPANSION PHASE: Patients must have a biopsiable lesion and provide consent for on treatment biopsy
* Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of AZD6738 in combination with DS-8201a in patients \< 18 years of age, children are excluded from this study
* Patients must have HER2-positive or HER2-expressing tumors determined by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. As a rule, for HER2 immunohistochemistry (IHC) scoring system trastuzumab for gastric cancer (TOGA) criteria used for gastric/gastroesophageal junction (GEJ) cancers will be employed (Note: in escalation phase, for breast cancer patients that are included, breast cancer criteria can be used). Specific requirement of HER2 status is outlined below:
* HER2 expression (1-3+) by IHC locally and confirmed centrally OR
* HER2 expression (1-3+) by IHC tested centrally OR
* HER2 amplification based on fluorescence in situ hybridization (FISH) or next generation sequencing
* Must have received at least one line of systemic chemotherapy for either locally advanced or metastatic disease and should have either progressed on this therapy or been intolerant to this therapy
* For tumors where anti-HER2 therapy is standard of care, patients must have progressed on at least 1 line of anti-HER2 therapy if eligible. For patients where DS8201a is approved as standard of care, prior treatment with DS8201a is not allowed
* Must have unresectable, advanced/metastatic disease
* Must have at least 1 measurable lesion on CT scan per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patient without measurable but evaluable disease are allowed for dose-escalation phase
* Must be willing and able to provide an adequate archival tumor sample available to confirm HER2 status by Central Laboratory (if local testing is used for enrollment), else must be willing and able to provide an adequate archival tumor sample for HER2 testing centrally
* Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
* Must have life expectancy of at least 3 months
* Must have left ventricular ejection fraction (LVEF) \>= 50% within 28 days before enrollment (study drug treatment) by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan
* Must have a negative pregnancy test (if female)
* Platelets \>= 100,000/mcL (within 14 days before enrollment)
* No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
* Hemoglobin \>= 9.0 g/dL (within 14 days before enrollment)
* Absolute neutrophil count \>= 1,500/mcL (within 14 days before enrollment)
* No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
* Creatinine clearance \> 45/mL/min (using the Cockcroft-Gault equation) (within 14 days before enrollment)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 5 x institutional upper limit of normal (ULN) (within 14 days before enrollment)
* Total bilirubin =\< 1.5 x ULN if no liver metastases or \< 3 x ULN with Gilbert's Syndrome or liver metastases at baseline (within 14 days before enrollment)
* Leukocytes \>= 3,000/mcL (within 14 days before enrollment)
* Albumin \> 2.5 g/dL (GEJ patients only) (within 14 days before enrollment)
* International normalized ratio (INR) and either partial thromboplastin time (PTT) or activated (a)PTT =\< 1.5 x ULN (within 14 days before enrollment)
* Must have adequate treatment washout period before study treatment, defined as: Major surgery (\>= 4 weeks), radiation therapy (\>= 3 weeks; in case of palliative radiation \>= 2 weeks), systemic therapy (\>= 3 weeks; in case of investigational drug use \>= 2 weeks or 5 half-lives, whichever is longer)
* Patients who are human immunodeficiency virus (HIV) positive may participate IF they meet the following eligibility requirements:
* They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
* They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count \< 200 cells/mcl over the past 2 years, unless it was deemed related to THE CANCER AND/OR CHEMOTHERAPY-induced bone marrow suppression
* For patients who have received chemotherapy in the past 6 months, a CD4 count \< 250 cells/mcl during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy
* They must have an undetectable viral load and a CD4 count \>= 250 cells/mcL within 7 days of enrollment
* They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months. HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Subjects with clinically inactive brain metastases may be included. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiation therapy and study treatment
* Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the investigator favors participation in the clinical trial
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as AZD6738 are known to be teratogenic; thus, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 7 months (women of childbearing potential \[WOCBP\] only) after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of study drug administration
* Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone \[FSH\] \> 40 mIU/mL and estradiol \< 40 pg/mL \[\< 147 pmol/L\] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
* Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 6 months after the final study drug administration. Preservation of sperm should be considered prior to enrolment in this study
* Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
* Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
Exclusion Criteria:
* Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Patient using e-cigarettes/vaping are also excluded
* Patients with a medical history of myocardial infarction within 6 months before enrollment (study treatment), symptomatic congestive heart failure (New York Heart Association Class II to IV, corrected QT interval (QTcF) prolongation to \> 470 ms (females) or \> 450 ms (males) as corrected by Framingham's formula
* Patients with spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
* Patients with multiple primary malignancies within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors
* Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product
* Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
* Patients with substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the investigator
* Patients with a concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator
* Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities grade \>1) with the exception of alopecia. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator after discussion with study principal investigator (PI) (e.g., grade 2 chemo-induced neuropathy).
* Any previous treatment with an ATR inhibitor
* Patients with any clinically apparent pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
* Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
* Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
* Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
* Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
* Patients with previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
* Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable within the last 28 days as long as they are not within 1 week prior to screening assessment)
* Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks (TIAs)
* Uncontrolled hypertension (grade 2 or above) requiring clinical intervention
* Patients with relative hypotension (\< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of \> 20 mm Hg
* Patients who have received corticosteroids (at a dose \> 10 mg prednisone/day or equivalent) for any reason within 2 weeks prior to first dose
* Patients with uncontrolled intercurrent illness
* Patients with psychiatric illness/social situations that would limit compliance with study requirements
* Pregnant women are excluded from this study because DS-8201a is a HER2 antibody conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DS-8201a, breastfeeding should be discontinued if the mother is treated with DS-8201a. These potential risks may also apply to AZD6738
* Patients cannot be receiving chloroquine or hydroxychloroquine. Patients receiving these drugs must have a washout period of \> 14 days before enrollment/randomization
Advanced Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Metastatic Breast Carcinoma, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Stage III Colon Cancer AJCC v8, Stage IV Colon Cancer AJCC v8, Advanced Endometrial Carcinoma, Clinical Stage IV Gastric Cancer AJCC v8, Anatomic Stage III Breast Cancer AJCC v8, Unresectable Malignant Solid Neoplasm, Stage III Uterine Corpus Cancer AJCC v8, Stage IV Uterine Corpus Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8, Metastatic Gastroesophageal Junction Adenocarcinoma, Stage III Colorectal Cancer AJCC v8, Advanced Breast Carcinoma, Advanced Colon Carcinoma, Advanced Colorectal Carcinoma, Advanced Gastric Carcinoma, Advanced Gastroesophageal Junction Adenocarcinoma, Advanced Salivary Gland Carcinoma, Clinical Stage III Gastric Cancer AJCC v8, HER2-Positive Breast Carcinoma, Malignant Hepatobiliary Neoplasm, Stage III Major Salivary Gland Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IV Major Salivary Gland Cancer AJCC v8, Unresectable Colorectal Carcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)
This is an open-label, first-in-human study designed to evaluate the safety, tolerability,
pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as
LOXO-292) administered orally to participants with advanced solid tumors, including
rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer
(MTC) and other tumors with RET activation.
For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical benefit
from standard therapy, or
• Decline standard therapy
• Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
• A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years)
with no sudden deterioration 2 weeks prior to the first dose of study treatment
• Adequate hematologic, hepatic and renal function
• Life expectancy of at least 3 months
For Phase 2: As for phase 1 with the following modifications:
• For Cohort 1: Participants must have received prior standard therapy appropriate for
their tumor type and stage of disease, or in the opinion of the Investigator, would be
unlikely to tolerate or derive clinical benefit from appropriate standard of care
therapy
• Cohorts 1 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene
alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate
to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers
with other RET alteration/activation may be allowed with prior Sponsor approval
• cfDNA positive for a RET gene alteration not known to be present in a tumor
sample
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who
discontinued another RET inhibitor may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET
fusion; determined to be medically operable and tumor deemed resectable by a thoracic
surgical oncologist, without prior systemic treatment for NSCLC
Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants
otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5
half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292
(selpercatinib). In addition, no concurrent investigational anti-cancer therapy is
permitted Note: Potential exception for this exclusion criterion will require a valid
scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 2 weeks prior to planned
start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292 (selpercatinib), with the exception of participants receiving
radiation to more than 30% of the bone marrow or with a wide field of radiation, which
must be completed at least 4 weeks prior to the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the
exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Participants are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28
days, 14 days if stereotactic radiosurgery (SRS)
• Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or
prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds
(msec)
• Participants with implanted pacemakers may enter the study without meeting QTc
criteria due to nonevaluable measurement if it is possible to monitor for QT
changes.
• Participants with bundle branch block may be considered for study entry if QTc is
appropriate by a formula other than Fridericia's and if it is possible to monitor
for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior
systemic therapy for NSCLC.
Drug: LOXO-292
Lymphoma, Non-Small Cell Lung Cancer, Colon Cancer, Medullary Thyroid Cancer, Any Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Small Intestine, Soft Tissue
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib, neo-adjuvant treatment in early stage NSCLC
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.
Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
• Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.
• ECOG PS 0-1.
• Age ≥18 (or age ≥ 20 of age as required by local regulation).
• Capability to swallow capsules intact (without chewing, crushing, or opening).
• At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.
• Prior cytotoxic chemotherapy is allowed.
• Prior immunotherapy is allowed.
• Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
• Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
• Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
without supplementation
• Life expectancy ≥ 3 months.
PHASE 2 Key Inclusion Criteria
• Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.
• Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:
• a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.
• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.
OR
• a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
• Age ≥12 (or age ≥ 20 as required by local regulation).
• Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.
• At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
(v1.1) are eligible.
• Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.
i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
• Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
• Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
supplementation
• Life expectancy ≥ 3 months.
Key Exclusion Criteria PHASE 1 and PHASE 2
• Concurrent participation in another therapeutic clinical trial.
• Symptomatic brain metastases or leptomeningeal involvement.
• History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.
• Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (≤10 fractions) must have been completed at least 48 hours prior to study
entry
• Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥2
• Any of the following cardiac criteria:
Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value Any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation
or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.
• Known active infections (bacterial, fungal, viral including HIV positivity).
• Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
• Peripheral neuropathy of CTCAE ≥grade 2.
• History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.
Stereotactic Radiosurgery (SRS) Dose-Escalation Study for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true
tolerable doses, which may exceed the current standard doses. This may lead to an improvement
in local control, patient survival, and/or quality-of life.
Inclusion Criteria
• Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ
cell cancer, or unknown primary tumor.
• Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or
intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI
contrast, an MRI without contrast is acceptable if lesions are visible)
• All brain metastases must be outside the brain stem (midbrain, pons and medulla).
• Patient must have 10 or less brain metastases.
• The maximum diameter of any lesion must be less than or equal to 3.0 cm.
• Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any
targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one
additional brain metastasis that can be targeted with SRS
• Age ≥ 18 years.
• ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or
better.
• All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.
A female of child-bearing potential is any woman (regardless of sexual orientation,
marital status, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
• Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria
• Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
• Patients with leptomeningeal metastasis.
NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive
CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal
involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal
enhancement by imaging (MRI) would be considered to have LMD even in the absence of
positive CSF cytology, unless a parenchymal lesion can adequately explain the
neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally
symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would
not be considered to have LMD. In that patient, CSF sampling is not required to
formally exclude LMD, but can be performed at the investigator's discretion based on
level of clinical suspicion.
• Patients with a contraindication to both MRI (with or without contrast) and CT scan
(with contrast)
• Patients with life expectancy < 3 months.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
• Subjects must not be pregnant or nursing at the time of SRS treatment due to the
potential for congenital abnormalities and the potential of this regimen to harm
nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Neoplasms, Adult, Malignant, Lymphoma, Sarcoma, Multiple Myeloma, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Cardiovascular, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Lymphoid Leukemia, Small Intestine, Soft Tissue
UT Southwestern; Parkland Health & Hospital System
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
This is a Phase 1 study of the combination of two drugs: MM-398 and Cyclophosphamide. The
goal is to find the highest dose of MM-398 that can be given safely when it is used together
with the chemotherapy drug Cyclophosphamide.
• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma,
neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid
Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of
a patient <18 years of age will provide informed consent and patients 11 to 18 years
of age will provide written assent or as per participating institutional policy.
Exclusion Criteria:
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled
blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for
pregnancy at the time of enrollment
Drug: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Neuroblastoma, Sarcoma, Ewing Sarcoma, Mycosis Fungoides, Rhabdomyosarcoma, Osteosarcoma, Recurrent or Refractory Solid Tumors, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Kaposis sarcoma, Other Hematopoietic, Small Intestine, Soft Tissue
Abatacept in Immune Checkpoint Inhibitor Myocarditis (ATRIUM)
The primary aim is to test whether abatacept, as compared to placebo, is associated with a
reduction in major adverse cardiac events (MACE) among participants hospitalized with
myocarditis secondary to an immune checkpoint inhibitor (ICI). The primary outcome, MACE, is
a composite of first occurrence of cardiovascular death, non-fatal sudden cardiac arrest,
cardiogenic shock, significant ventricular arrythmias, significant bradyarrythmias, or
incident heart failure.
• Must have provided informed consent in a manner approved by the Investigator's
Institutional Review Board (IRB) prior to any study-related procedure being performed.
If a participant is unable to provide informed consent due to his/her medical
condition, the participant's legally authorized representative may consent on behalf
of the study participant, as permitted by local law and institutional Standard
Operating Procedures;
• Aged greater than or equal to 18 years at the time of informed consent;
• Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as
administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis),
alone or in combination with other cancer therapies (i.e. chemotherapy, radiation
therapy or targeted therapy). The FDA-approved ICI could be given as part of a
clinical trial but not in combination with a new investigational agent which may cause
myocarditis;
• A diagnosis of myocarditis.
• Hospitalized at the time of randomization;
• On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg
of solumedrol per day for myocarditis within 24 hours of first administration of study
drug;
• Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial
injury will be defined as an institutional troponin (either conventional or
high-sensitivity troponin I or T, using the standard institutional assay) with a value
that is ≥5 times the upper limit of the reference standard normal for that
institution. The troponin assay may be adjusted based on sex depending on
institutional standards. This value of troponin of ≥5 times above the institutional
upper limits of normal value must be noted within 10 days prior to potential
randomization. The 10-day period can be in the outpatient or inpatient setting. For
example, a participant with a troponin value that on one occasion was ≥5 times the
upper limits of institutional normal in the 10-day window prior to potential
randomization (whether in the inpatient or outpatient setting), but later decreases
below that threshold, typically due to starting corticosteroids, would still be
considered eligible;
• The following laboratory parameters, not older than 48 hours at the time of
randomization, and measured as part of usual care:
• Total white blood cell (WBC) count >2,500/μl
• Absolute neutrophil count (ANC) >1,500/μL
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <20 times the
upper limit of the institutional normal ranges;
• Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized)
must have a negative highly sensitive urine or serum pregnancy test prior to
randomization. Participating women of childbearing potential must be willing to
consistently use effective methods of contraception from screening until at least 90
days after administration of the last dose of study drug. Participating men must also
be willing to consistently use effective methods of contraception from screening until
at least 90 days after administration of the last dose of study drug; and
• Must be willing and able to abide by all study requirements and restrictions.
Exclusion Criteria:
• Must not have experienced any of the following (as defined in the section on the
primary endpoint) in the 30-day period prior to randomization:
• A sudden cardiac arrest
• Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II
second degree atrioventricular block or third degree (complete) atrio-ventricular
(AV) block, for which an intervention with a temporary or permanent pacemaker is
completed or recommended).
• A significant tachyarrhythmia (ventricular fibrillation of any duration or
sustained ventricular tachycardia (>30 seconds, >120 beats per minute); or a
ventricular tachyarrhythmia requiring intervention.
• Recent (≤2 month) exposure to abatacept or belatacept.
• Concurrent or recent (≤2 month) use of the following non-corticosteroid
immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT inhibitors
(including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib),
tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and plasma exchange. The
use of intravenous immunoglobulin is permitted prior to randomization and during study
treatment.
• Currently enrolled in another interventional study utilizing systemic agents for the
management of ICI-related toxicities.
• Female who is pregnant, breastfeeding, or is considering becoming pregnant during the
study or for approximately 90 days after the last dose of study drug.
• Male who is considering fathering a child or donating sperm during the study or for
approximately 30 days after the last dose of study drug.
• Any active, chronic, or recurrent viral infection that, based on the investigator's
clinical assessment, makes the participant an unsuitable candidate for the study.
These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or
disseminated (even a single episode) herpes zoster, and disseminated (even a single
episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface
antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid
(DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core antibody
(HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA) detectable in any
participant with anti-HCV antibody (HCV Ab). Patients with active Covid-19 infection
will be excluded. This is defined as the period of ongoing symptoms in the setting of
a positive Covid-19 test, or until 10 days after symptom onset and after resolution of
fever for at least 24 hours, without the use of fever-reducing medications.
• Known active tuberculosis (TB), history of incompletely treated TB, suspected or known
extrapulmonary TB, suspected or known systemic bacterial or fungal infections;
• Receipt of any live vaccine within four weeks prior to the first dose of study drug,
or expected need of live vaccination during study participation including at least 90
days after the last dose of IV study drug.
• Any medical condition that could interfere with, or for which the treatment might
interfere with, the conduct of the study or interpretation of the study results, or
that would, in the opinion of the Investigator, increase the risk of the participant
by participating in the study.
• Any factors that, in the Investigator's opinion, are likely to interfere with study
procedures, such as history of noncompliance with scheduled appointments.
Drug: Abatacept plus, Drug: Placebo
Cancer, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Thyroid, Urinary Bladder, Small Intestine, Soft Tissue, Unknown Sites, Myocarditis Acute