• Ability to comprehend and willingness to sign a written ICF for the study. Women 18 years of age or older (or as applicable per local country requirements).
• Histologically confirmed diagnosis of advanced or metastatic endometrial cancer with disease progression on or after treatment with at least 1 platinum-containing regimen for advanced or metastatic disease.
• Groups A and B: Have not been previously treated with a PD-(L)1 inhibitor.
• Group A only: Tumor tissue tested as MSI-High
• Group B only: Tumor tissue tested as deficient MMR or an ultra-mutated POLE tumor.
• Group D only: Tumor tissue tested as having an FGFR 1,2,3 mutation or alteration characterized as per protocol.
• Must have at least 1 measurable tumor lesion per RECIST v1.1.
• Willing to provide tumor tissue sample (fresh or archived).
• ECOG performance status 0 to 1.
• Willingness to avoid pregnancy.
• Group A only: Histologically confirmed diagnosis of carcinosarcoma of the uterus.
• Histologically confirmed diagnosis of sarcoma of the uterus.
• Has disease eligible for potentially curative treatment.
• Receipt of anticancer therapy within 28 days of the first administration of study treatment, with the exception of localized radiotherapy.
• Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline unless approved by the medical monitor.
• Groups C and D (combinations): limiting immune-related toxicity during prior checkpoint inhibitor therapy.
• Has an active autoimmune disease requiring systemic immunosuppression with corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs within 14 days before the first dose of study treatment.
• Receiving chronic systemic steroids (> 10 mg/day of prednisone or equivalent):
• Known active CNS metastases and/or carcinomatous meningitis.
• Has known active hepatitis B or C.
• Has received a live vaccine within 28 days of the planned start of study treatment.
• Evidence of interstitial lung disease or active, noninfectious pneumonitis.
• Participants who are known to be HIV-positive with some protocol exceptions.

• Patients must have recurrent or persistent endometrial carcinoma, which is refractory to curative therapy or established treatments; histologic confirmation of the original primary tumor is required; patients with the following histologic epithelial cell types are eligible: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.); NOTE: clear cell histology is excluded
• Patients must have evaluable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or non-measurable (detectable) disease
• Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be > 15 mm in short axis when measured by CT or MRI; patients with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST version 1.1; tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy
• Non-measurable (detectable) disease in a patient is defined in this protocol as one who does not have measurable disease but has at least one of the following conditions:
• Ascites and/or pleural effusion attributed to tumor;
• Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
• Patients must have signed an approved informed consent and authorization permitting release of personal health information
• Patients must have had one prior chemotherapeutic regimen for management of endometrial carcinoma; initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy; chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen
• Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease according to the following definition: cytotoxic regimens include any agent that targets the genetic and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to the bone marrow and/or gastrointestinal mucosa; Note: patients on this non-cytotoxic study are allowed to receive one additional cytotoxic chemotherapy regimen for management of recurrent or persistent disease, as defined above; however, patients are encouraged to enroll on second-line non-cytotoxic studies prior to receiving additional cytotoxic therapy
• Patients may have received non cytotoxic therapy including immunotherapy (1 prior line in either upfront or recurrent setting) but excluding cediranib, olaparib, AZD5363 (capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and pembrolizumab for the management of recurrent or persistent disease; prior hormonal therapy is allowed; hormonal therapy for grade 1 endometrial cancers with low volume or indolent disease is encouraged
• Bevacizumab, or one course of single-agent immune-checkpoint therapy, excluding durvalumab (MEDI4736), is permitted prior to enrollment on this trial
• Body weight > 30 kg
• Age >= 18
• The trial is open to females only (including women with an intact uterus with uterine cancer); fertile females of childbearing potential need to agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation, and have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2 (Karnofsky >= 60%) within 7 days prior to registration; patients should have no deterioration over the previous two weeks
• Hemoglobin >= 10 mg/dL with no blood transfusion in the past 28 days (within 28 days prior to administration of study drug)
• Platelet count >= 100 x 10^9/L (within 28 days prior to administration of study drug)
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (within 28 days prior to administration of study drug)
• Patients must have creatinine clearance estimated of >= 51 mL/min using the Cockcroft Gault equation or based on a 24-hour urine test (within 28 days prior to administration of study drug)
• Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days prior to administration of study drug)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (within 28 days prior to administration of study drug)
• Urine protein: creatinine (UPC) < 1 or < 2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also have UPC < 0.5 on 2 consecutive samples (within 28 days prior to administration of study drug)
• Patients must be able to swallow and retain oral medications and without gastrointestinal illnesses that would preclude absorption of cediranib, olaparib, or AZD5363 (capivasertib)
• Patients must have adequately controlled blood pressure (BP), with a BP no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility; patients must have a BP of =< 140/90 mmHg taken in the clinic setting by a medical professional within 2 weeks prior to starting study; patients with hypertension may be managed with up to a maximum of three antihypertensive medications; it is strongly recommended that patients who are on three antihypertensive medications be followed by a cardiologist or blood pressure specialist for management of blood pressure while on protocol
• Note: Patients must be willing and able to check and record daily blood pressure readings
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential as confirmed by a negative urine or serum pregnancy test within 7 days prior to start of investigational products (IPs); postmenopausal is defined as:
• Age >= 60 years, or
• Age < 60 with any one or more of the conditions below:
• Amenorrheic for >= 1 year in the absence of chemotherapy and/or hormonal treatments,
• Luteinizing hormone and/or follicle stimulating hormone and/or estradiol levels in the post-menopausal range
• Radiation-induced oophorectomy with last menses > 1 year ago,
• Chemotherapy-induced menopause with > 1 year interval since last menses,
• Surgical sterilization (bilateral oophorectomy or hysterectomy)
• Patients must have a life expectancy of greater than 16 weeks
• Patients with a previous diagnosis of immune or inflammatory colitis or chronic diarrhea > 1 month without immune or inflammatory colitis are eligible with adequately controlled colitis (no diarrhea greater than grade 1 for at least 28 days) and in the absence of symptoms related to colonic dysfunction; patients who required steroids for prior immune related colitis are not eligible
• Females of child-bearing potential should use two forms of highly reliable methods of contraception from the time of screening until 4 weeks after discontinuing study treatment.
• Acceptable methods of contraception include:
• Established use of oral, injected or implanted hormonal methods of contraception.
• Placement of an intrauterine device or intrauterine system.
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
• Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
• True abstinence (i.e., not engaging in sexual activity for the total duration of study treatment and the treatment washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control).
• Bilateral tubal occlusion or salpingectomy
• Acceptable non-hormonal birth control methods include:
• Total/True abstinence: When the patient refrains from any form of sexual intercourse and this is in line with their usual and/or preferred lifestyle; this must continue for the total duration of the trial and for at least 1 month after the last dose of study drug <>. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods, or declaration of abstinence solely for the duration of a trial) and withdrawal are not acceptable methods of contraception]
• Vasectomised sexual partner PLUS male condom. With participant assurance that partner received post-vasectomy confirmation of azoospermia.
• Tubal occlusion PLUS male condom
• Intrauterine device (IUD) PLUS male condom. Provided coils are copper-banded.
• Acceptable hormonal methods:
• Normal and low dose combined oral pills PLUS male condom.
• Cerazette (desogestrel) PLUS male condom. Cerazette is currently the only highly efficacious progesterone-based pill.
• Hormonal shot or injection (e.g., Depo-Provera) PLUS male condom.
• Etonogestrel implants (e.g., Implanon, Norplant) PLUS male condom.
• Norelgestromin/EE transdermal system PLUS male condom
• Intrauterine system [IUS] device (e.g., levonorgestrel releasing IUS -Mirena) PLUS male condom.
• Intravaginal device (e.g., EE and etonogestrel) PLUS male condom

Exclusion Criteria:

• Prior enrollment into a clinical trial including cediranib or olaparib; Note: prior bevacizumab is not an exclusion criterion
• Prior enrollment into a clinical trial including cediranib, olaparib, AZD5363 (capivasertib), durvalumab (MEDI4736), or the combination of lenvatinib and pembrolizumab. Note: Prior bevacizumab or single-agent immune checkpoint blockade, excluding durvalumab (MEDI4736), is not an exclusion criterion
• Prior chemotherapy, endocrine therapy, radiotherapy, or investigational agents within 4 weeks
• More than one prior line of treatment with immune checkpoint blockade therapy
• Current signs/symptoms of bowel obstruction and/or signs/symptoms of bowel obstruction within the preceding 3 months
• History of gastrointestinal perforation; patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired or has healed, there has been no evidence of fistula for at least 6 months, and patient is deemed to be at low risk of recurrent fistula
• Uncontrolled intercurrent illness including, but not limited to known ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or psychiatric illness/social situations that would limit compliance with study requirements
• Concomitant use of known strong cytochrome (CYP) 3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout period prior to starting study treatments is 2 weeks for strong inhibitors, and at least 1 week for moderate inhibitors
• Concomitant use of potent inhibitors or inducers of CYP3A4 within 2 weeks before the start of study treatment (3 weeks for St John's wort), or sensitive substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week before the start of study treatment. Concomitant use of drugs known to prolong the QT interval within 5 half-lives of the first dose of study treatment
• Pregnant women are excluded from this study because cediranib and olaparib are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with cediranib and olaparib, breastfeeding should be discontinued if the mother is treated with cediranib or olaparib; these potential risks may also apply to other agents used in this study; for women of childbearing capacity a negative pregnancy test is required
• Known human immunodeficiency virus (HIV)-positive individuals are ineligible because of the potential for pharmacokinetic interactions between many anti-HIV drugs and cediranib, olaparib, and/or AZD5363 (capivasertib); in addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Known active hepatitis B or hepatitis C infection on antiviral treatment
• Prior history of stroke or transient ischemic attack within the last 6 months
• Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) per institutional guidelines, or < 55%, if threshold for normal not otherwise specified by institutional guidelines, for patients with the following risk factors:
• Prior treatment with anthracyclines
• Prior treatment with trastuzumab
• Prior central thoracic radiation therapy (RT), including exposure of heart to therapeutic doses of ionizing RT
• History of myocardial infarction within 6-12 months prior to start of IPs
• Prior history of other significant impaired cardiac function
• Patients with any of the following:
• History of myocardial infarction within 6 months prior to starting treatment
• Unstable angina
• Resting electrocardiogram (ECG) with clinically significant abnormal findings or with corrected QT interval (QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
• New York Heart Association functional classification of III or IV
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Major surgical procedure within 4 weeks prior to starting treatment; patients must have recovered from any effects of any major surgery and surgical wound should have healed prior to starting treatment
• History of intra-abdominal abscess within 3 months prior to starting treatment
• Patients may not use any complementary or alternative medicines including natural herbal products or folk remedies as they may interfere with the effectiveness of the study treatments
• No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUBCT)
• Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable)
• Patients with myelodysplastic syndrome (MDS)/treatment-related acute myeloid leukemia (t-AML) or with features suggestive of MDS/AML
• Central nervous system metastases:
• Symptomatic uncontrolled brain metastases requiring corticosteroid treatment; history of spinal cord compression unless after definitive treatment the patient has clinically stable disease (SD) for at least 28 days prior to starting IPs; in the absence of these features and in an asymptomatic patient a scan to confirm the absence of brain metastases is not required
• Other malignancy within the last 5 years except for:
• Curatively treated basal cell or squamous cell carcinoma of skin; in situ cancer of the cervix, ductal carcinoma in situ of the breast or stage 1, grade 1 endometrial carcinoma
• Curatively treated other solid tumors including lymphomas (without bone marrow involvement) with no evidence of disease for >= 5 years prior to start of IPs
• Persisting >= grade 2 Common Terminology Criteria for Adverse Events (CTCAE) toxicity (except alopecia and grade 2 peripheral neuropathy) from previous anti-cancer treatment(s)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cediranib, olaparib, AZD5363 (capivasertib), or durvalumab (MEDI4736)
• Pneumonitis or moderate-severe pre-existing pulmonary disease
• Patients who have a diagnosis of immunodeficiency or are receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days of enrollment.
• Premedication with steroids for CT scan contrast is allowed.
• Inhaled or topical corticosteroids are allowed.
• The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed.
• The use of physiologic doses of corticosteroids may be approved after consultation with the study chair
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. This includes, but is not limited to, patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease
• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible
• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice)

All study parts:
• Participants must be willing to provide adequate archival tissue sample
• Participants must be willing to use highly effective birth control
• Participants must have adequate organ function
• Participants must be able to swallow capsules Dose escalation- Participants must have one of the following:
• Parts A and B: ER+ HER2- breast cancer with evidence of locally advanced unresectable or metastatic disease who have had the following:
• Part A: may have had up to 1 prior regimen of any kind for in the advanced/metastatic setting and no prior cyclin-dependent kinase 4/6 (CDK4/6) inhibitor therapy.
• Part B: may have had up to 2 prior regimens, no more than 1 of which may be endocrine therapy in the advanced/metastatic setting, and must have received a prior CDK4/6 inhibitor
• Cohort E4: No prior everolimus.
• Cohort E5: No prior alpelisib and must have a phosphatidylinositol 3-kinase catalytic α (PIK3Cα) mutation as determined by local testing.
• Part C: ER+, human epidermal growth factor receptor 2 positive (HER2+) breast cancer with evidence of locally advanced unresectable or metastatic disease who have had at least 2 HER2-directed therapies in any setting.
• Part D: ER+, EEC that has progressed after platinum containing chemotherapy and no prior fulvestrant or aromatase inhibitor therapy.
• Part E: ER+ and HER2+ breast cancer with evidence of locally advanced, unresectable, or metastatic disease.
• Part E: Participants must have received induction taxane chemotherapy combined with trastuzumab + pertuzumab as first-line treatment for advanced/metastatic disease and must not have progressed on this regimen.
• Part E: Participants must not have received more than 1 HER2-directed regimen or any endocrine therapy for advanced disease or any prior CDK4/6 inhibitor therapy. Participants with ER+/HER2- breast cancer enrolled in this study must have had evidence of clinical benefit while on endocrine therapy for at least 24 months in the adjuvant setting or at least 6 months in the advanced/metastatic setting or have untreated de novo metastatic breast cancer
• Participants must not have certain infections such as hepatitis or tuberculosis or HIV that are not well controlled
• Participants must not have another serious medical condition
• Participants must not have cancer of the central nervous system that is unstable
• Participants must not be pregnant or breastfeeding

• Patient is at least 18 years of age
• Patient with advanced or metastatic solid tumor and has disease progression after treatment with available therapies that are known to confer clinical benefit or who are intolerant to treatment that meets the following requirements for the part of the study they will participate in: 1. Part 1: Patient with any advanced or metastatic solid tumor 2. Part 2A: Patient with any advanced or metastatic solid tumor 3. Part 2B: Patient with Non-Small Cell Lung Cancer (NSCLC) and Endometrial cancers
• Female patients, if of childbearing potential, must have a negative serum pregnancy test within 72 hours prior to the date of the first dose of study medication.
• Female patients of childbearing potential must agree to use 2 adequate methods of contraception with their partner starting with the screening visit through 150 days after the last dose of study therapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 for Part 1 and ≤ 1 for Part 2. Adequate organ function.
• Patient has received prior therapy with an anti- programmed death receptor 1 (anti-PD-1), anti-PD-1- ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD- L2) agent.
• Known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a patient from study participation regardless of clinical stability.
• Known additional malignancy that progressed or required active treatment within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell cancer (SqCC) of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
• Known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (eg, hepatitis C virus ribonucleic acid (HCV RNA) (qualitative) is detected).
• Active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease- modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• History of interstitial lung disease.

• Histological confirmed primary SCC of the vulva
• T1 tumor, not encroaching urethra/vagina/anus
• Depth of invasion > 1mm
• Tumor diameter < 4cm
• Unifocal tumor
• No enlarged (>1.5cm) or suspicious inguinofemoral lymph nodes at imaging (CT/MRI/ultrasound)
• Possibility to obtain informed consent
• Metastatic sentinel lymph node; size of metastasis > 2mm and / or extracapsular extension, or
• Metastatic sentinel lymph node: more than 1 SN with metastasis ≤ 2mm
• Patients are able to understand requirements of study, provide written informed consent and comply with the study and follow-up procedures
• Adequate bone marrow, renal and liver function:
• Absolute neutrophil count ≥ 1.5 x 109 /L
• Platelet count ≥ 100 x 109 /L
• Creatinine clearance ≥ 40 ml/min measured by the Cockroft Gault formula
• Total bilirubin < 1.25 x ULN Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN
• Performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale (Appendix A)
• Age 18 years or older
• Life expectancy of ≥ 12 weeks
• Written informed consent
• Inoperable tumors and tumors > 4cm
• Multifocal tumors
• Tumors with other pathology than squamous cell carcinoma
• Patients with enlarged / suspicious lymph nodes which are proven metastatic after fine needle aspiration cytology
• No other carcinomas, other than basal cell carcinomas, within last 5 years
• History of pelvic radiotherapy
• History of any infection requiring hospitalization or antibiotics within 2 weeks before enrollment
• Pregnant female or nursing mother
• Desire to become pregnant
• Known brain or spinal cord metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids
• Unstable angina, myocardial infarction, cerebrovascular accident, > Class II congestive heart failure according to the New York Heart Association Classification for Congestive Heart Failure (see Appendix B) within 6 months before enrollment

• 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.
• 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.

• Participants must be at least 18 years of age or older.
• Participants must have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic solid tumor(s).
• Participants must have tested positive for a pathogenic or likely pathogenic tPALB2 gene mutation using a CLIA-certified laboratory as described in the Next-Generation Sequencing (NGS) Laboratory Manual.
• Participants who have stable and asymptomatic Central Nervous System (CNS) disease must be receiving a stable (for at least 7 days) or decreasing corticosteroid dose at the time of study entry.
• Participants must submit fresh or archived (collected within 24 months of enrollment) Formalin-Fixed Paraffin-Embedded (FFPE) tumor sample to the central laboratory for post-enrollment confirmation of tPALB2 status.
• Participants must have received all standard therapies appropriate for their tumor type and stage of disease or, in the opinion of the Investigator, the patient would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, or the participant has no satisfactory alternative treatments.
• Participants have other active concomitant malignancy that warrants systemic, biologic, or hormonal therapy.
• Participants who have ovarian or prostate cancer.
• Participants who have variants of undetermined significance (VUS), but not pathogenic variants of PALB2, at the time of screening.
• Participants who relapsed while receiving platinum based therapy in the adjuvant/curative setting.
• Participants progressing within 14-18 weeks while receiving platinum based therapy in the metastatic setting.
• Participants who have received Poly (ADP-ribose) polymerase (PARP) inhibitor(s) in prior lines of treatment.
• Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain metastases, or radiologic signs of CNS hemorrhage.
• Participants with germline or somatic BRCA1 or BRCA2 mutations.
• Participant has systolic blood pressure (BP) over 140 mmHg or diastolic BP over 90 mmHg, despite optimal medical therapy.
• Participants have previously or are currently participating in a treatment study of an investigational agent within 3 weeks of the first dose of therapy preceding the study.
• Participants have received prior systemic cytotoxic chemotherapy, biological therapy, or hormonal therapy for cancer, or received radiation therapy within 3 weeks of the first dose therapy preceding the study.

• Patients with histologically confirmed solid tumor malignancies with residual tumors present that require standard of care chemotherapy for a minimum number of cycles. All anatomical sites and all tumor histologies are eligible including central nervous system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8
•25 years
• In the opinion of the investigator, patients must be thought to be able to lie still for imaging without sedation for 20
•30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
• Patients with known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment in the study. Relapsed patients are eligible prior to starting their relapsed chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).

• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line therapy without having achieved a prior partial or complete remission OR Biopsy proven residual disease at the completion of planned standard initial front-line therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or complete remission
• Newly diagnosed high risk disease, defined as having an expected event free survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for profiling from diagnosis or progression / recurrence --- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started matched targeted therapy based on the report .
• No Therapy Planned -- Patients who have declined further anticancer therapy will be excluded.
• Performance Status -- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be excluded.

Inclusion Criteria 1. Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ cell cancer, or unknown primary tumor. 2. 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) 3. All brain metastases must be outside the brain stem (midbrain, pons and medulla). 4. Patient must have 10 or less brain metastases. 5. The maximum diameter of any lesion must be less than or equal to 3.0 cm. 6. 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 7. Age ≥ 18 years. 8. ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or better. 9. 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). Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring: Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a substance that kills sperm) 10. Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria 1. Patients had craniotomy and surgery to the brain within 7 days from the date of SRS. 2. 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. 3. Patients with a contraindication to both MRI (with or without contrast) and CT scan (with contrast) 4. Patients with life expectancy < 3 months. 5. 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. 6. 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.

Inclusion: 1. Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging. 2. Age ≥2 and <21 years at the time of study entry. 3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age. 4. Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed). 5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits. 6. Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome. 7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component). 8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia. 9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit. Exclusion: 1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible. 2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. 3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.) 4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 5. Prior irradiation to >50% of the bone marrow (see Appendix 9). 6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry. 7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries. 8. For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX. 9. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days. 10. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable. 11. Hereditary bone marrow failure disorder. 12. QTc >470 msec. 13. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%. 14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy). 15. Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study. 16. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.

• 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 > 1410 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
• 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)

• 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.
• 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