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A Study of Avutometinib (VS-6766) v. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer With and Without a KRAS Mutation (RAMP-201)
This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy and in
combination with Defactinib in subjects with recurrent Low-Grade Serous Ovarian Cancer
(LGSOC)
• Histologically proven LGSOC (ovarian, peritoneal)
• In Part A KRAS mutation, KRAS wt
• Progression or recurrence of LGSOC after at least one prior systemic therapy for
metastatic disease.
• Measurable disease according to RECIST 1.1
• An Eastern Cooperative Group (ECOG) performance status ≤ 1.
• Adequate organ function
• Adequate recovery from toxicities related to prior treatments
• Agreement to use highly effective method of contraceptive
Exclusion Criteria:
• Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy
• Co-existing high-grade ovarian cancer or another histology
• History of prior malignancy with recurrence <3 years from the time of enrollment
• Major surgery within 4 weeks
• Symptomatic brain metastases requiring steroids or other interventions
• Known SARS-Cov2 infection (clinical symptoms) ≤28 days prior to first dose of study
therapy
• For subjects with prior MEK exposure, Grade 4 toxicity deemed related to the MEK
inhibitor
• Active skin disorder that has required systemic therapy within the past year
• History of rhabdomyolysis
• Concurrent ocular disorders
• Concurrent heart disease or severe obstructive pulmonary disease
• Subjects with the inability to swallow oral medications
Drug: avutometinib (VS-6766), Drug: avutometinib (VS-6766) and Defactinib
A Study to Compare Two Surgical Procedures in Individuals With BRCA1 Mutations to Assess Reduced Risk of Ovarian Cancer (SOROCk)
This clinical trial studies how well two surgical procedures (bilateral salpingectomy and
bilateral salpingo-oophorectomy) work in reducing the risk of ovarian cancer for individuals
with BRCA1 mutations. Bilateral salpingectomy involves the surgical removal of fallopian
tubes, and bilateral salpingo-oophorectomy involves the surgical removal of both the
fallopian tubes and ovaries. This study may help doctors determine if the two surgical
procedures are nearly the same for ovarian cancer risk reduction for women with BRCA1
mutations.
• Individuals 35-50 years of age, inclusive
• Patients who are undergoing risk-reducing salpingo-oophorectomy (RRSO) (for the BSO
arm) and patients who have declined or elected to defer BSO after proper counselling
to clearly explain the standard of care for BRCA1 mutation carriers and are undergoing
salpingectomy (for the BLS arm with delayed oophorectomy arm). Concurrently planned
hysterectomy with either arm is permitted
• At least one intact ovary and fallopian tube is in situ at the time of counseling and
consent. Prior hysterectomy is allowed provided it did not include bilateral
salpingectomy. Prior tubal ligation is allowed if one intact ovary and fallopian tube
(with fimbria not removed) are present
• Positive Clinical Laboratory Improvement Act (CLIA)-approved test results for
pathogenic or likely pathogenic germline BRCA1 mutation in the patient. Documentation
of the result is required
• Patients may be premenopausal or menopausal
• Transvaginal ultrasound (TVUS) and CA-125 within 180 days of registration
• The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry
• Individuals who are currently pregnant or plan to become pregnant in the future
through assisted reproductive technologies and who have received proper counseling are
eligible. Individuals who are currently pregnant and plan bilateral salpingectomy at
the time of a planned cesarean section are eligible. Patients must understand that
they will not be able to become pregnant naturally in the future
Exclusion Criteria:
• Individuals with a history of any prior cancer who have received chemotherapy within
the past 30 days or radiotherapy to abdomen or pelvis at any prior time
• Prior history of ovarian cancer, including low malignant potential neoplasms (LMP),
primary peritoneal carcinoma, or fallopian tube carcinoma
• Patients medically unfit for the planned surgical procedure
• Patients with abnormal screening tests (TVUS, CA-125) suspicious for occult or gross
pelvic malignancy or neoplasm within the past 180 days
• An abnormal TVUS is defined as morphologic or structural variations suspicious
for ovarian malignancy or complex cystic lesions (simple cysts < 5 cm in maximal
diameter are not exclusionary)
• An abnormal CA-125 is defined as a level > 50 U/ml in premenopausal individuals
if they are not current users of oral contraceptives; an abnormal CA-125 is
defined as a level > 40 U/ml for premenopausal individuals who are current users
of oral contraceptives. An abnormal CA-125 is defined as a level > 35 U/ml in
postmenopausal individuals.
Active Surveillance, Bleomycin, Etoposide, Carboplatin or Cisplatin in Treating Pediatric and Adult Patients With Germ Cell Tumors
This phase III trial studies how well active surveillance help doctors to monitor subjects
with low risk germ cell tumors for recurrence after their tumor is removed. When the germ
cell tumors has spread outside of the organ in which it developed, it is considered
metastatic. Drugs used in chemotherapy, such as bleomycin, carboplatin, etoposide, and
cisplatin, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. The trial studies
whether carboplatin or cisplatin is the preferred chemotherapy to use in treating metastatic
standard risk germ cell tumors.
• There is no age limit for the low risk stratum (stage I ovarian immature teratoma and
stage I non-seminoma or seminoma malignant GCT [all sites])
• Standard risk 1: Patient must be < 11 years of age at enrollment
• Standard risk 2: Patients must be >= 11 and < 25 years of age at enrollment
• Patients enrolling on one of the low risk arms must be newly diagnosed with a stage I
germ cell tumor; for the standard risk arms, patients must be newly diagnosed with
metastatic germ cell tumor (stage II or higher); histologic confirmation of a primary
extracranial germ cell tumor in any of the categories outlined below is required of
all patients at enrollment except for those who were initially diagnosed with stage I
non-seminoma malignant GCT and later recur during observation post surgery off study;
for these patients, if elevated tumor markers rise to > 5 x upper limit of normal
(ULN) on at least 2 measurements taken at least 1 week apart, a diagnostic biopsy is
not required for enrollment
• Low risk stage I immature teratoma (IT); site: ovarian; stage: Children's Oncology
Group (COG) stage I, Federation of Gynecology and Obstetrics (FIGO) stage IA and IB;
grade: 2 or 3; histology: pure immature teratoma (may contain microscopic foci of yolk
sac tumor), mixed immature and mature teratoma, (no pathological evidence of MGCT);
tumor markers: alpha-FP =< 1,000 ng/mL, beta-HCG institutional normal; all ages
• Low risk stage I non-seminoma MGCT; site: ovarian, testicular, or extragonadal; stage:
COG stage I, FIGO stage IA and IB, American Joint Committee on Cancer (AJCC)
testicular stage IA, IB and IS; histology: must contain at least one of the following:
yolk sac tumor, embryonal carcinoma, or choriocarcinoma (pure or mixed); all ages
• Low risk stage I seminoma-MGCT; site: testicular; stage: COG stage I; AJCC testicular
stage IA IB, and IS; histology: must contain at least one of the following: may
contain immature/mature teratoma; may NOT contain yolk sac tumor, embryonal carcinoma,
or choriocarcinoma; all ages
• Standard risk 1 (SR1); site: ovarian, testicular, or extragonadal; stage: COG stage
II-IV, FIGO stage IC, FIGO stage II-IV (International Germ Cell Consensus
Classification [IGCCC] criteria DO NOT apply); histology: must contain at least one of
the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age (years) <
11
• Standard risk 2 (SR2)
• Site: ovarian; stage: COG stage II and III, FIGO stage IC, II and III; histology:
must contain at least one of the following: yolk sac tumor, embryonal carcinoma,
or choriocarcinoma; age (years) >= 11 and < 25
• Site: testicular; stage: COG stage II-IV, AJCC stage II, III, IGCCC good risk;
histology: must contain at least one of the following: yolk sac tumor, embryonal
carcinoma, or choriocarcinoma; tumor markers: must be IGCCC good risk; post op:
alpha-FP < 1,000 ng/mL, beta-HCG < 5,000 IU/mL and lactate dehydrogenase (LDH) <
3.0 x normal; age (years) >= 11 and < 25
• Site: extragonadal; stage: COG stage II; histology: must contain at least one of
the following: yolk sac tumor, embryonal carcinoma, or choriocarcinoma; age
(years) >= 11 and < 25
• Notes:
• IGCCC criteria only apply to SR2 patients with a testicular primary tumor
• Use post-op tumor marker levels to determine IGCCC risk group
• Stage 1 seminoma patients are not eligible for the standard risk arms of the
study
• For the low risk stage I non-seminoma MGCT and the standard risk arms, components
of yolk sac tumor, embryonal carcinoma, or choriocarcinoma can be mixed with
other forms of GCT, such as seminoma or mature or immature teratoma; if yolk sac
tumor is the only malignant component present, then it must be deemed by the
pathologist to be greater than a "microscopic component" of yolk sac tumor
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1, 2 or 3; use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age
• Organ function requirements apply ONLY to patients who will receive chemotherapy (SR1
and SR2 patients)
• Adequate renal function defined as:
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 (within 7 days prior to enrollment) OR
• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
(mg/dL)
• 1 month to < 6 months male: 0.4 female: 0.4
• 6 months to < 1 year male: 0.5 female: 0.5
• 1 to < 2 years male: 0.6 female: 0.6
• 2 to < 6 years male: 0.8 female: 0.8
• 6 to < 10 years male: 1 female: 1
• 10 to < 13 years male: 1.2 female: 1.2
• 13 to < 16 years: male: 1.5 female: 1.4
• >= 16 years male: 1.7 female: 1.4
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
upper limit of normal (ULN) for age (for the purpose of this study, the ULN for SGPT
is 45 U/L) (within 7 days prior to enrollment)
• Peripheral absolute neutrophil count (ANC) >= 1,000/mm^3 (within 7 days prior to
enrollment) AND
• Platelet count >= 100,000/mm^3 (within 7 days prior to enrollment)
• Patients enrolling on the standard risk arms must be medically fit to receive protocol
treatment and with no contraindications to protocol treatment
• Eligibility criteria to participate in the pilot study of the AYA-Hears instrument
(patient reported outcomes [PROs] of ototoxicity) Note: participants in group 1 will
not receive AGCT1531 protocol-directed therapy; all other AYA-HEARS patients must be
enrolled on the AGCT1531 SR2 arm in order to participate
• >= 11 and < 25 years old at enrollment
• Able to fluently speak and read English
• Has received prior cisplatin- or carboplatin-based chemotherapy regimen for malignancy
including diagnoses other than germ cell tumor
• Followed for cancer or survivorship care at one of the following institutions:
• Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
• Dana Farber/Harvard Cancer Center
• Hospital for Sick Children
• Children's Hospital of Eastern Ontario
• Oregon Health and Science University
• Seattle Children's Hospital
• Yale University
Exclusion Criteria:
• Patients with any diagnoses not listed including:
• Stage I testicular cancer patients who have undergone primary RPLND
(retroperitoneal lymph node dissection)
• Pure dysgerminoma
• Pure mature teratoma
• Pure immature teratoma COG stage I, grade I
• Pure immature teratoma COG stage I, grade 2,3 with alpha-fetoprotein (AFP) >=
1000 ng/mL
• Pure immature teratoma COG stage II •IV or FIGO stage IC to IV
• "Poor risk" GCT (age >= 11 years old and COG stage IV ovarian, COG stage III or
IV EG, or IGCCC intermediate or poor risk testicular), or
• Primary central nervous system (CNS) germ cell tumor
• Germ cell tumor with somatic malignant transformation
• Spermatocytic seminoma
• Patients must have had no prior systemic therapy for the current cancer diagnosis
• Patients must have had no prior radiation therapy with the exception of CNS
irradiation of brain metastases; (this exception only applies to SR1 patients; any
patients over age 11 with distant metastases to brain [stage IV disease] would be
considered poor risk and therefore not eligible for this trial)
• Patients with significant, pre-existing co-morbid respiratory disease that
contraindicate the use of bleomycin are ineligible for the standard risk arms of the
trial
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs; a pregnancy test is required for female
patients of childbearing potential; (this criteria applies ONLY to patients who will
receive chemotherapy [SR1 and SR2 patients])
• Lactating females who plan to breastfeed their infants; (this criteria applies ONLY to
patients who will receive chemotherapy [SR1 and SR2 patients])
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation; (this
criteria applies ONLY to patients who will receive chemotherapy [SR1 and SR2
patients])
Childhood Extracranial Germ Cell Tumor, Malignant Germ Cell Tumor, Germ Cell Tumor, Extragonadal Embryonal Carcinoma, Stage I Ovarian Choriocarcinoma, Stage II Ovarian Choriocarcinoma, Stage III Ovarian Choriocarcinoma, Stage IV Ovarian Choriocarcinoma, Testicular Mixed Choriocarcinoma and Embryonal Carcinoma, Testicular Mixed Choriocarcinoma and Teratoma, Testicular Mixed Choriocarcinoma and Yolk Sac Tumor, Stage I Testicular Choriocarcinoma AJCC v6 and v7, Stage I Testicular Embryonal Carcinoma AJCC v6 and v7, Stage I Testicular Yolk Sac Tumor AJCC v6 and v7, Stage II Testicular Choriocarcinoma AJCC v6 and v7, Stage II Testicular Embryonal Carcinoma AJCC v6 and v7, Stage II Testicular Yolk Sac Tumor AJCC v6 and v7, Stage III Testicular Choriocarcinoma AJCC v6 and v7, Stage III Testicular Embryonal Carcinoma AJCC v6 and v7, Stage III Testicular Yolk Sac Tumor AJCC v6 and v7, Malignant Ovarian Teratoma, Stage I Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage I Ovarian Teratoma AJCC v6 and v7, Stage I Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage II Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage II Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage III Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage III Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage IV Ovarian Embryonal Carcinoma AJCC v6 and v7, Stage IV Ovarian Yolk Sac Tumor AJCC v6 and v7, Stage I Testicular Seminoma AJCC v6 and v7
UT Southwestern; Children’s Health; Parkland Health & Hospital System
Letrozole With or Without Paclitaxel and Carboplatin in Treating Patients With Stage II-IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
This phase III trial studies how well letrozole with or without paclitaxel and carboplatin
works in treating patients with stage II-IV low-grade serous carcinoma of the ovary,
fallopian tube, or peritoneum. Letrozole is an enzyme inhibitor that lowers the amount of
estrogen made by the body which in turn may stop the growth of tumor cells that need estrogen
to grow. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different
ways to stop the growth of tumor cells, either by killing the cells, by stopping them from
dividing, or by stopping them from spreading. It is not yet known whether giving letrozole
alone or in combination with paclitaxel and carboplatin works better in treating patients
with low-grade serous carcinoma of the ovary, fallopian tube, or peritoneum compared to
paclitaxel and carboplatin without letrozole.
• Patients must have the psychological ability and general health that permits
completion of the study requirements and required follow up
• All women will, by definition, be considered menopausal due to surgical removal of
both ovaries prior to trial enrollment
• Patients must have newly diagnosed, stage II-IV low-grade serous ovarian cancer
(submission of pathology report[s] required). Ovarian cancer = ovarian, fallopian tube
and primary peritoneal cancers. p53 immunohistochemistry (IHC) is required and must
show nonaberrant pattern (nonaberrant p53 expression is consistent with
normal/wildtype TP53). If aberrant p53 expression is found on p53 IHC, the patient is
NOT eligible (aberrant p53 expression is consistent with mutant TP53 and supports
diagnosis of high grade serous ovarian cancer). A copy of the pathology report that
includes the diagnosis of low grade serous ovarian cancer and nonaberrant p53 IHC
result must be submitted in RAVE
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 14 days prior to registration
• Contrast-enhanced imaging of the chest, abdomen and pelvis within 28 days prior
to registration
• Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with
either optimal (=< 1 cm diameter residual disease/nodule) or suboptimal residual
disease (> 1 cm diameter residual disease/nodule) status allowed
• Patients must have undergone a bilateral salpingo-oophorectomy
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0, 1 or 2 within 14 days prior to registration
• Patients must be within =< 8 weeks of primary cytoreductive surgery at time of
randomization
• Patients must be able to take per oral (P.O.) medications
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (within 14 days
prior to registration)
• Platelets greater than or equal to 100,000 cells/mcl (within 14 days prior to
registration)
• Creatinine less than or equal to 1.5 x upper limit of normal (ULN) (within 14 days
prior to registration)
• Bilirubin less than or equal to 1.5 x ULN (within 14 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
to 3 x ULN (within 14 days prior to registration)
• The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry and, for patients treated in the United States
(U.S.), authorization permitting release of personal health information
Exclusion Criteria:
• 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
• Patients may not have received neoadjuvant chemotherapy or radiotherapy for the
treatment of this disease
• Patients may not have received previous hormonal therapy for the treatment of this
disease
• Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to
carboplatin/paclitaxel therapy
• Patients with severe cardiac disease:
• Myocardial infarction or unstable angina within 6 months prior to registration
• New York Heart Association (NYHA) class II or greater congestive heart failure
• Patients with known central nervous system metastases
• Patients with active (except for uncomplicated urinary tract infection) or
uncontrolled systemic infection
• Patients with >= grade 2 baseline neuropathy
• Known human immunodeficiency virus (HIV)-infected patients on effective
anti-retroviral therapy with undetectable viral load within 6 months are eligible for
this trial
Phase 1/2a Evaluation of Adding AL3818 to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma (AL3818-US-002) (AL3818)
This trial is a Phase 1b/2a trial designed to evaluate the safety and efficacy of adding oral
AL3818 to standard platinum-based chemotherapy concurrently and continued as a maintenance
therapy for up to 12 months.
• Female ≥ 18 years
• Previously histologically proven diagnosis of
a. Endometrial Cancer: recurrent or persistent endometrial carcinoma refractory to
conventional therapy or established treatments with the following histologic
epithelial cell types i. Endometrioid adenocarcinoma, serous adenocarcinoma,
undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma,
adenocarcinoma not otherwise specified, mucinous adenocarcinoma, squamous cell
carcinoma, and transitional cell carcinoma b. Ovarian Cancer: recurrent or persistent
ovarian or primary peritoneal cancer refractory to established treatments with the
following histologic epithelial cell types i. Endometrioid adenocarcinoma, serous
adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed
epithelial carcinoma, adenocarcinoma not otherwise specified.
c. Cervical cancer: squamous cell carcinoma of the cervix refractory to conventional
therapy or established treatments with the following histologic epithelial cell types:
i. Squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma Measurable
disease defined as at least one lesion that can be accurately measured in at least one
dimension (longest dimension to be recorded). Each lesion must be ≥ 20mm when measured
by conventional techniques, including palpation, plain x-ray, CT, and MRI or ≥ 10mm
when measured by spiral CT.
• Life expectancy ≥ 3 months
• Able to take orally administered study medication
• Must sign approved informed consent and authorization permitting release of personal
health information.
• Patient must have adequate:
1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm^3, equivalent to
Common Toxicity Criteria (CTC) grade 1, platelets ≥ 100,000/mm^3
2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN), CTC
grade 1. Note: If creatinine is > 1.5 x ULN, creatinine clearance must be > 50
mL/min.
3. Hepatic function: bilirubin ≤ 1.5 x ULN (CTC grade 1) or ≤ 3.0 x ULN for subjects
with Gilbert Syndrome; AST and ALT ≤ 3.0 ×ULN.
4. Coagulation profile: PT such that international normalized ratio (INR) is ≤ 1.55
(or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times
control.
5. ECOG performance ≤ 2
• Patient of child-bearing potential must agree to use contraceptive measures starting 1
week before the administration of the first dose of AL3818 until 4 weeks after
discontinuing study drug and have a negative serum pregnancy test prior to study entry
and cannot be lactating.
• Ability and willingness to comply with the study protocol for the duration of the
study and with follow-up procedures.
Exclusion Criteria:
• Patients with serious, non-healing wound, ulcer or bone fracture.
• Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels.
• Patient with history or evidence upon physical examination of CNS disease, including
primary brain tumor, seizures not controlled with standard medical therapy, any brain
metastases or history of cerebrovascular accident (CVA, stroke) transient ischemic
attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment
on this study.
a. Patients with metastatic CNS tumors may participate in this trial, if the patient
is > 4 weeks from therapy completion (including radiation and/or surgery), is
clinically stable at the time of study entry and is not receiving corticosteroid
therapy.
• Patients with proteinuria: patients discovered to have a urine protein of 1+ on
dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection, which
must be an adequate collection and must demonstrate < 1000 mg protein/24 hours to
allow participation in the study.
• Patients with clinically significant cardiovascular disease including uncontrolled
hypertension, myocardial infarction or unstable angina within 6 months prior to
registration. New York Heart Association (NYHA) Grade II or greater congestive heart
failure, Serious cardiac arrhythmia requiring medication, Grade II or greater
peripheral vascular disease.
• Patients who are pregnant or nursing.
• Women of childbearing potential who are unable to use contraceptive measures during
study therapy and for at least 3 months after completion of AL3818 therapy.
• Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• Hemoptysis within 3 months prior to first scheduled dose of AL3818.
• Patients with acute or chronic liver disease, active hepatitis A or B with known
cirrhosis or liver dysfunction.
• Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in
cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of AL3818
or a major surgical procedure within 28 days or minor surgical procedure performed
within 7 days prior to first scheduled dose of AL3818.
• Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19
who cannot be switched to other alternative medications .
• Known history of human immunodeficiency virus infection (HIV).
• Subjects with active bacterial infections (other than uncomplicated urinary tract
infection) and/or receiving systemic antibiotics.
• Patients with other invasive malignancies, with the exception of non-melanoma skin
cancer, who had (or have) any evidence of other cancer present within the last 5 years
or whose previous cancer treatment contraindicates this protocol therapy.
• History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer
disease within the past 3-months that in the opinion of the investigator may place the
patient at risk of side effects on an anti-angiogenesis product.
• History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
• Intra-abdominal abscess within the last 3 months.
• Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken
at least one hour apart, defined as systolic bloodpressure (BP) >160 mm Hg or
diastolic BP > 90 mm Hg pressure.
• QTcF>470 msec on screening ECG.
• A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family
history of Long QT Syndrome).
• The use of concomitant medications that prolong the QT/QTc interval. Baseline
echocardiogram (within 2 months) with left ventricular ejection fraction (LVEF) < 50%.
• History of difficulty swallowing, malabsorption, active partial or complete bowel
obstruction, or other chronic gastrointestinal disease or condition that may hamper
compliance and/or absorption of AL3818.
• History of pancreatitis and/or renal disease or pancreatitis that includes
histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial
nephritis, crystal nephropathy, or other renal insufficiencies.
• Treatment with an investigational agent within the longest time frame of either 5
half- lives or 30 days of initiating study drug.
• Known recreational substance abuse.
• Known hypersensitivity to AL3818 or components of the formulation.
A Study of ZN-c3 in Participants With Solid Tumors
This is a Phase 1/2 open-label, multicenter study, evaluating the safety, tolerability,
efficacy, pharmacokinetics (PK) and pharmacodynamics of ZN-c3 alone and in combination with
other drugs.
In order to be eligible to participate in any phase of this study, an individual must meet
all of the following criteria:
1. Provision of written informed consent.
2. Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of
informed consent.
3. Adequate hematologic and organ function as defined by the following criteria:
1. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; excluding measurements obtained
within 7 days after daily administration of filgrastim/sargramostim or within 3
weeks after administration of pegfilgrastim.
2. Platelet count ≥ 100 × 10^9/L; excluding measurements obtained within 3 days
after transfusion of platelets.
3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper
limit of normal (ULN). If liver function abnormalities are due to underlying
liver metastases, AST and ALT ≤ 5 x ULN.
4. Total serum bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in the case of Gilbert's disease.
5. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min.
4. Female subjects of childbearing potential must have a negative serum beta human
chorionic gonadotropin test.
5. Male subjects and female subjects of childbearing potential must agree to use an
effective method of contraception per institutional standard prior to the first dose
and for 90 days after the last dose of ZN-c3.
Individuals must meet the additional criteria in order to be eligible to participate in
Phase 1:
1. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
2. Measurable or evaluable disease per RECIST version 1.1.
Individuals must meet these additional criteria in order to be eligible to participate in
Phase 2 Single Agent part of the study:
1. ECOG performance status ≤ 1.
2. Measurable disease per RECIST version 1.1.
Individuals must meet these additional criteria in order to be eligible to participate in
Phase 2 combination with a PARP inhibitor:
1. ECOG performance status ≤ 1.
2. Measurable disease per RECIST version 1.1.
Individuals must meet these additional criteria in order to be eligible to participate in
Phase 2 combination with a PD-1 inhibitor:
1. ECOG performance status ≤ 1.
2. Measurable disease per RECIST version 1.1.
Key
Exclusion Criteria:
1. Any of the following treatment interventions within the specified time frame prior to
Cycle 1 Day 1:
1. Major surgery within 28 days.
2. Radiation therapy within 21 days.
3. Any prior systemic therapy regardless of the stop date, but the subject must have
recovered to eligibility levels from prior toxicity.
4. Autologous or allogeneic stem cell transplant within 3 months.
5. Current use of an investigational agent that is not expected to be cleared by the
first dosing of study drug or that has demonstrated to have prolonged side
effects. Subjects should have recovered from the side effects to a Grade 0 or 1
(except alopecia).
2. A serious illness or medical condition(s) including, but not limited to, the
following:
1. Brain metastases that require immediate treatment or are clinically or
radiologically unstable.
2. Leptomeningeal disease that requires or is anticipated to require immediate
treatment.
3. Myocardial impairment of any cause resulting in heart failure by New York Heart
Association Criteria Class III or IV.
4. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
study drug administration, or may interfere with the interpretation of study
results, and in the judgment of the Investigator would make the subject
inappropriate for entry into this study.
5. Significant gastrointestinal abnormalities
6. Active or uncontrolled infection.
3. Unresolved toxicity of Grade > 1 attributed to any prior therapies (excluding Grade 2
neuropathy, alopecia or skin pigmentation).
4. Prior therapy with ZN-c3 or known hypersensitivity to any drugs similar to ZN-c3 in
class.
5. Subjects with active (uncontrolled, metastatic) second malignancies or requiring
therapy.
Drug: ZN-c3
Small Cell Lung Cancer, Fallopian Tube Cancer, Non Small Cell Lung Cancer, Malignant Melanoma, Metastatic Breast Cancer, Triple Negative Breast Cancer, Epithelial Ovarian Cancer, Urothelial Carcinoma, Solid Tumor, Corpus Uteri, Peritoneal Cancer
• Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancy.
• Progressed or was intolerant to all available therapies known to confer clinical
benefit appropriate for their tumor type, and for which the patient was eligible and
willing to receive, or refused SOC treatments that are perceived to have marginal
clinical benefit.
• Adequate bone marrow, kidney and liver function.
• Performance status of 0 or 1.
• Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1
except for AEs not constituting a safety risk by Investigator judgement.
Exclusion Criteria:
• Prior treatment targeting ILT2 and/or ILT4 or targeting HLA-G.
Drug: NGM707, Drug: NGM707 plus pembrolizumab, Drug: NGM707, Drug: NGM707, Drug: NGM707, Drug: NGM707 plus pembrolizumab, Drug: NGM707 plus pembrolizumab
Esophageal Cancer, Breast Cancer, Melanoma, Gastric Cancer, Colorectal Cancer, Ovarian Cancer, Glioblastoma, Cervical Cancer, Renal Cell Carcinoma, Non Small Cell Lung Cancer, Mesothelioma, Cholangiocarcinoma, Pancreatic Ductal Adenocarcinoma, Brain and Nervous System, Breast - Female, Breast - Male, Kidney, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Skin, Ovary, Pancreas, Squamous Cell Carcinoma of Head and Neck, Endocervical Cancer