-Patients initially diagnosed with low-grade serous ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas OR
-Patients initially diagnosed with serous borderline ovarian or peritoneal carcinoma that recur as low-grade serous carcinoma (invasive micropapillary serous carcinoma or invasive grade I serous carcinomas
-Patients must have documented low-grade serous carcinoma; confirmation must occur by prospective pathology review prior to study entry; the prospective pathology review must be done on tissue from the recurrent carcinoma
-At least 4 weeks must have elapsed since any major surgery
-All patients must have measurable disease
-Patients must have recurred or progressed following at least one platinum-based chemotherapy regimen
-Patients may have received an unlimited number of prior therapy regimens
-Patients may not have received all of the five choices in the "standard therapy" arm
-Patients must have a GOG performance status of 0 or 1
-If letrozole is selected as the control therapy, patients must be postmenopausal
-No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
-If patients have had a potential index lesion radiated, it must have progressed post radiation therapy to be used as a measurable eligibility lesion
-Patients may not have received prior MEK, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor therapy
-Patients with known leptomeningeal or brain metastases or spinal cord compression should be excluded from this clinical trial

-Patients must have pathologically proven non-small cell lung cancer (all histologic types) confirmed by tumor biopsy and/or fine-needle aspiration. Disease must be Stage IV as defined in Section 4.0 , or recurrent. The primary diagnosis of non-small cell lung cancer should be established using the current WHO/IASLC-classification of Thoracic Malignancies.
-Patients must either be eligible to be screened at progression on prior treatment or to be pre-screened prior to progression on current treatment.
-Screening at progression on prior treatment:

--To be eligible for screening at progression, patients must have received at least one line of systemic therapy for any stage of disease (Stages I-IV) and must have progressed during or following their most recent line of therapy.

-Pre-Screening prior to progression on current treatment:

--To be eligible for pre-screening, current treatment must be for Stage IV or recurrent disease and patient must have received at least one dose of the current regimen. Patients must have previously received or currently be receiving a platinum-based chemotherapy regimen or anti-PD-1/PD-L1 therapy, alone or in combination (e.g. Nivolumab or Pembrolizumab). Patients on first-line treatment are eligible upon receiving Cycle 1, Day 1 infusion.

Note: Patients will not receive their sub-study assignment until they progress and the LungMAP Notice of Progression is submitted.
-Patients must have adequate tumor tissue available, defined as ? 20% tumor cells and ? 0.2 mm3 tumor volume.

• The local interpreting pathologist must review the specimen.

• The pathologist must sign the LungMAP

Local Pathology Review Form confirming tissue adequacy prior to Step 1 registration.
-Patients must agree to have this tissue submitted to Foundation Medicine for common broad platform CLIA biomarker profiling, PD-L1, and c-MET IHC (see Section 15.2). If archival tumor material is exhausted, then a new fresh tumor biopsy that is formalin-fixed and paraffin-embedded (FFPE) must be obtained. Patients who need the fresh biopsy must also submit whole peripheral blood for ctDNA testing. A tumor block or FFPE slides 4-5 microns thick must be submitted. Bone biopsies are not allowed. If FFPE slides are to be submitted, at least 12 unstained slides plus an H&E stained slide, or 13 unstained slides must be submitted. However, it is strongly recommended that 20 FFPE slides be submitted. Note: Previous next-generation DNA sequencing (NGS) will be repeated if done outside this study for sub-study assignment.
-Patients must agree to have any tissue that remains after testing retained for the use of sub-study Translational Medicine (TM) studies at the time of consent the patient is enrolled in.
-Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have progressed following all standard of care targeted therapy. EGFR/ALK/ROS/BRAF testing is not required prior to Step 1 registration, as it is included in the Foundation One testing for screening/pre-screening.
-Patients must have Zubrod performance status 0-1 (see Section 10.2) documented within 28 days prior to Step 1 registration.

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health IHA (Ann Arbor, Brighton, Canton, Chelsea), Livonia, Genesys

Eligibility Criteria:

 3.3.1 Documentation of Disease

Patients must have a morphologically-confirmed diagnosis of MDS with an IPSS-R score ≥4 (See Appendix VI for IPSS-R scoring) [2]. Patients must have a detectable pathogenic IDH2 mutation based on the NCI Myeloid Panel. 

3.3.2 Prior Treatment 

-No prior treatment with DNA methyltransferase inhibitors (ASTX727, azacitidine, or decitabine). 

-Prior treatment with growth factors (ESA, g-CSF, TPO agonist), lenalidomide or luspatercept is allowed with a maximum limit of 1 month of exposure.

-Patients with therapy-related MDS are allowed.

3.3.3 Age ≥ 18 years

3.3.4 ECOG Performance Status ≤ 2

3.3.5 Required Initial Laboratory Values

-Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)*

-AST (SGOT)/ALT (SGPT) ≤ 3.0 x upper limit of normal (ULN)

-GFR ≥ 30 mL/min/1.73m2**  

 *Unless elevated due to Gilbert’s syndrome. In patients with Gilbert’s syndrome, if the total bilirubin is ≤ 3.0 × ULN, then they are eligible for enrollment.

**To be calculated using Cockroft Gault formula.

3.3.6 Not pregnant and not nursing, because this study involves: an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done as part of screening lab work prior to registration is required.

3.3.7 Comorbid Conditions

-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.

-HIV: HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial.

-Hepatitis B: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

-Hepatitis C: 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 

**PLEASE SEE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST** 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health IHA ( Ann Arbor, Brighton, Canton, Chelsea) and Livonia, Genesys, Hurley, Lehigh

Eligibility Criteria:

3.1.1 Patient must be ≥ 60 years of age or adults ? 60 who in the opinion of the treating physician are better served by azanucleoside-based therapy rather than intensive, cytarabine-based induction based on clinical status (i.e., performance status, age >75 years), organ dysfunction, or disease biology.

3.1.2 Patient must have a morphologically confirmed diagnosis of AML according to the WHO 2016 classification excluding APL with PML\u0002RARA, AML with RUNX1-RUNX1T1, or AML with CBFB-MYH11.

3.1.3 Patient must have no prior therapy for AML with the exception of hydroxyurea and all-trans retinoic acid (ATRA), or leukapheresis. Patients with cytarabine-based emergency therapy prior to the start of therapy on this trial are eligible.

3.1.4 Patient must have no prior therapy with hypomethylating agents or FLT3 inhibitors.

3.1.5 Patient must have the FLT3-ITD or D835 mutation based on MyeloMATCH Master Screening and Reassessment Protocol (MSRP) 

3.1.6 Patient must be assigned to this protocol by the myeloMATCH MSRP.

3.1.7 Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.

All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.

A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Patient of child bearing potential? ______ (Yes or No)

Date of blood test or urine study: ___________ 

3.1.8 Patient of childbearing potential and/or sexually active patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Contraception measures must continue for 30 days after the last dose of Venetoclax for all patients and for 6 months after the last dose of Gilteritinib for patients of childbearing potential and for 4 months after the last dose of Gilteritinib for male patients with partners of childbearing potential. Patient must not breastfeed during treatment and for 2 months after treatment ends.

3.1.9 Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision\u0002making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible. 

3.1.10 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration/randomization are eligible for this trial.

3.1.11 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

3.1.12 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.

3.1.13 Patient must not have the medical necessity for ongoing treatment with a strong CYP3A4 inducing drug.

3.1.14 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. 

 **PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health SJMH IHA (Brighton, Ann Arbor, Canton, Chelsea) Livonia, Genesys

Eligibility Criteria:

5.1. Disease Related Criteria

a. Participants must have been registered to the MYELOMATCH Master Screening and Reassessment Protocol prior to consenting to this study. Participants must have disease with a detectable IDH2 mutation based on central testing through the MYELOMATCH and be assigned to this clinical trial via MATCHBox prior to registration to this study. Note: Pre-enrollment/diagnosis labs must have already been performed under MYELOMATCH. See Section 18.5 for details.

b. Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) defined by having ≥ 20% blasts in the bone marrow and/or peripheral blood, excluding acute promyelocytic leukemia (APL) with PML-RARA.

5.2. Prior/Concurrent Therapy Criteria

a. Participants must not be receiving or planning to receive any other investigational agents while on protocol therapy.

b. Participants must not have received prior therapy for AML or MDS and/or MPN with the exception of hydroxyurea, all-trans retinoic acid (ATRA), colony\u0002stimulating factors, erythropoiesis-stimulating agents, immunosuppressive therapy, intrathecal chemotherapy, a single dose of cytarabine for cytoreduction, and/or leukapheresis.

c. Participants must not be currently receiving any cytarabine-containing therapy other than up to 1 g/m2 of cytarabine, which is allowed for urgent cytoreduction. The use of prior hydroxyurea, all-trans retinoic acid (ATRA), BCR-ABL directed tyrosine kinase inhibitor, erythropoiesis-stimulating agent, thrombopoietin receptor agonist and lenalidomide are allowed. Participants may receive hydroxyurea prior to treatment assignment on this substudy for cytoreduction but must agree to discontinue hydroxyurea prior to beginning treatment on this substudy.

1. WBC must be < 25 x 109 /L. Hydroxyurea, leukapheresis, and cytarabine < 1 g/m2 are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped prior to initiation of protocol therapy.

5.3. Clinical/Laboratory Criteria

a. Participants must be ≥ 60 years old; OR must be ≥ 18 years old and considered not eligible for cytarabine-based induction therapy.

b. Participants must have Zubrod Performance Status of 0-3 as determined by a history and physical (H&P) exam completed within 14 days prior to registration (see Section 10.6).

c. Participants must have a complete medical history and physical exam within 14 days prior to registration.

d. Participants must have adequate organ function as defined below within 14 days prior to registration:

- total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) unless history of Gilbert’s syndrome. Participants with history of Gilbert’s syndrome must have total bilirubin ≤ 3 x institutional ULN.

- AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN, unless considered to be elevated due to disease involvement.

** PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health IHA- Ann Arbor, Brighton, Canton, Chealsea, and Livonia, GenHur, Lehigh

Eligibility Criteria:

4.1.1 Participants must have been registered to Master Screening and Re-Assessment Protocol (myeloMATCH MSRP) prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox Protocol Assignment Team, prior to registration to this study. Participants must have agreed to have specimens submitted for translational medicine (MRD) and must be offered the opportunity to submit biosamples for banking for future research as per the myeloMATCH MSRP. Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP. See Appendix IX.

4.1.2 Previously untreated, de novo AML defined by >20% myeloblasts in the peripheral blood or bone marrow ( refer to the 2016 updated WHO classification of Myeloid Neoplasms and Acute leukemia) excluding all the following categories of AML (a through g):

a. Favorable cytogenetics: (t(8;21)q22;q22.1); RUNX1-RUNX1T1, inversion 16(p13.1;q22), t(16;16)(p13.1;q22);CBFB-MYH11

b. CEBPA biallelic mutations

c. NPM1 mutation

d. AML with PML-RARa

e. AML with any adverse cytogenetics, TP53 mutation, RUNX1 mutation, ASXL1, 11q23/KMT2 rearrangements

f. AML with FLT3-ITD or FLT3-TKD mutations

g. Therapy related AML, or AML following a diagnosis of myelodysplasia or myeloproliferative neoplasm Participants with CNS disease are eligible for this trial and will be treated according to institutional guidelines with intrathecal chemotherapy for this aspect of their disease.

4.1.3 Age 18-59 years at time of induction therapy 

4.1.4 ECOG performance status ≤ 3.

4.1.5 Patients must have adequate organ function as defined below (must be done within 7 days of enrollment):

a. total bilirubin ≤ 2x institutional upper limit of normal (ULN)

b. AST (SGPT) +/or ALT (SGOT) ≤3 × institutional ULN

c. Cardiac ejection fraction ≥ 50% (echocardiography or MUGA)

d. Calculated Creatinine Clearance ≥30 mL/min/ 1.73m2. Clearance to be calculated using Cockcroft formula.

4.1.6 WBC must be 25x109 /L. Hydroxyurea and leukapheresis are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped at least 24 hours prior to the initiation of protocol therapy.

4.1.7 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.

4.1.8 Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

 **PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED: Trinity Health IHA ( Ann Arbor, Brighton, Canton, Chelsea) and Livonia, Genesys, Hurley, Lehigh

Eligibility Criteria:

5.1 Step 1 Registration

a. Disease Related Criteria

1. Participants must have been registered to Master Screening and Re-Assessment Protocol, myeloMATCH MSRP, prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study. Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP. See Appendix 18.1 for details.

2. Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) per WHO criteria.

3. Participants must have high-risk (adverse) AML per ELN 2017 criteria. (7) Participants with therapy-related AML (t-AML), or with AML evolving from an antecedent hematologic disorder (such as myeloproliferative neoplasm), or AML with myelodysplasia-related changes (AML-MRC) are eligible. See Appendix 18.7 for details.

4. Acute promyelocytic leukemia is excluded.

5. Participants with favorable or intermediate risk disease are excluded.

6. Participants with FLT3 mutations (ITD or TKD) are excluded.

7. Participants with t(9;22) translocation are excluded. 

b. Prior/Concurrent Therapy Criteria

1. A single dose of intrathecal chemotherapy is allowed prior to study entry.

2. Prior anthracycline therapy is allowed but must not exceed a cumulative lifetime dose of 200 mg/m2 daunorubicin or equivalent (see Appendix 18.3 for anthracycline conversion table). Prior HMA exposure is allowed, as long as not for AML diagnosis.

3. Participants must not have received or be currently receiving any prior therapy for acute myeloid leukemia. Hydroxyurea to control the WBC is allowed prior to registration and initiation of protocol-defined therapy. All trans retinoic acid (ATRA) given until a diagnosis of acute promyelocytic leukemia is ruled out is also allowed.

4. Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy.

c. Clinical/Laboratory Criteria

1. Participants must be between 18 and 59 years of age.

2. Participants must have Zubrod Performance Status ≤ 3 as determined by an H&P completed within 14 days prior to registration. See Section 10.5.

3. Participants must have a complete medical history and physical exam within 7 days prior to registration.

4. Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications.

5. Participants with known HIV-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months prior to registration.

6. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to registration and be on suppressive therapy, if indicated.  

**PLEASE SEE THE CURRENT VERSION OF THE PROTOCOL FOR FULL ELIGIBILITY LIST**