Subprotocol Z1I eligibility (in addition to master):
-Patients must have mutation in the BRCA1 or BRCA2 gene in the tumor as determined by the MATCH screening assessment.

Patients with tumor carrying mutations defined as variants of uncertain significance will not qualify
-Patients with ovarian cancer must have received a PARP inhibitor as part of or as one of their prior lines of therapy
-Resting corrected QTc interval using the Fridericia formula (QTcF) should be < 450 msec/male and < 470 msec/female

-Patients must fulfill all eligibility criteria outlined in Section 3.1 of MATCH Master Protocol (excluding Section 3.1.6) at the time of registration to treatment step (Step 1, 3, 5, 7).
-Patients must have an AKT mutation as determined via the MATCH Master Protocol and described in Appendix II. See Appendix II for information on the AKT mutation and corresponding Levels of
Evidence.

-Patients with hormone receptor positive, defined as estrogen receptor and/or progesterone receptor > 1% by immunohistochemistry19, AND HER2 negative unresectable breast cancer, with no overexpression by IHC or amplification by in-situ hybridization20, are allowed to continue fulvestrant or an aromatase inhibitor (anastrazole, letrozole, exemestane) with Ipatasertib if patient just progressed on this antiestrogen therapy. GnRH agonists (such as leuprolide or goserelin) are
allowed.

- Patients with castration-resistant prostate cancer should maintain castrate levels of testosterone (i.e., with GnRH agonists or through surgical castration).
-Patients must not have known hypersensitivity to Ipatasertib or compounds of similar chemical or biologic composition.
-Patients with known KRAS, NRAS, HRAS, or BRAF mutations are not eligible for this protocol, as these mutations may lead to limited response due to resistance.
-Patients with diabetes or risk for hyperglycemia are eligible. Patients with diabetes mellitus should be on a stable dose of oral hypoglycemic agents for ? 4 weeks and appropriate diet.
-Prior PI3K and mTOR inhibitors are allowed, including in the metastatic setting
-Patients with a history of inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) or active diverticulitis are not eligible.

- Patients may not have received strong inhibitors or potent inducers or substrates of CYP3A4/5 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort).

-Patients must fulfill all eligibility criteria outlined in Section 3.1 of MATCH Master Protocol (excluding Section 3.1.6) at the time of registration to treatment step (Step 1, 3, 5, 7).
-Patients must have a BRAF non-V600 mutation or BRAF fusion, or another BRAF aberration, as determined via the MATCH Master Protocol and according to Appendix II.

- Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment assignment and must have no clinically important abnormalities in rhythm, conduction or morphology of resting ECG
-Patients must not have known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to BVD-523FB (ulixertinib), dimethyl sulfoxide (DMSO), or excipients.
-Patients must not have a left ventricular ejection fraction (LVEF) < the institutional lower limit of normal (LLN) or < 50% (whichever is higher).
-Patients must not have prior use of MEK or ERK 1/2 inhibitors.

-Patients must not have a history of RVO or central serous retinopathy. Patients with visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein thrombosis or central serous retinopathy will be excluded.
-Intraocular pressure is ? 21mm Hg as measured by tonography. Patients diagnosed with glaucoma within 1 month prior to Step 1 Registration are excluded.

-Patients must not have leptomeningeal metastases or spinal cord compression due to disease.
-Patients must not have primary malignancy of the central nervous system.

*DTL Required

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health (Ann Arbor, Canton, Chelsea, Brighton) Livonia, Genesy's, Hurley, Sparrow, Oakland, Lehigh Valley

Eligibility Criteria:

1. Patient must have measurable disease. 

2.Patient must have an ECOG performance status between 0-2. OR Patient must have Lansky performance status of ≥ 50% or Karnofsky performance status of ≥ 50%.

3. Patient must be deemed potentially eligible for a ComboMATCH Treatment Trial as assessed by the enrolling provider.

4. All patients must have sequencing results available from an NCI credentialed Designated Laboratory (DL).

5 Patients must have locally advanced or advanced histologically documented solid tumors requiring therapy and meet one of the following criteria: • Patients must have progressed on at least one line of standard systemic therapy. OR Patients whose disease has no standard treatment that has been shown to prolong overall survival.

 *****Please see the current version of protocol for full eligibility list*****

 **Cohort 1 Temporary Closed to Accrual Effective 04/01/2025**

**Cohort 3 Temporary Closed to Accrual Effective 07/03/2024**

 **Cohort 4 Temporary Closed to Accrual Effective 09/05/2024**

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED:  Trinity Health- SJMH (Ann Arbor, Brighton, Canton, Chelsea) and Livonia, Genesys, Hurley, Sparrow, SJMO

Eligibility Criteria:

3.3.1 Documentation of Disease: Histologically confirmed cancer for each cohort for which curable treatment modalities are not an option (see Section 3.2.3). Rare BRAF fusions and non-BRAF V600E aMOIs are acceptable. __

3.3.2 Measurable disease as defined in Section 11.0. Measurable disease per RECIST 1.1. There is a mandatory baseline biopsy for all ComboMATCH studies. Hence, patient must have a biopsiable lesion at baseline. Of note, in the case when a baseline biopsy is done after scans are obtained, a lesion separate from one that is biopsied needs to be measurable per RECIST 1.1. All radiologic studies must be performed within 28 days prior to randomization. ___

3.3.3 Cohort Specific Eligibility

Cohort 1

• Low grade serous ovarian cancer with KRAS, NRAS, non-BRAF V600E aMOIs or rare RAF fusions are acceptable.

• No prior MEK inhibitor or CDK4/6 inhibitor therapy.

• Any number of prior therapies permitted.

• No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks of the first dose of study therapy.

• No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to the start of study treatment 

Cohort 2

• Low grade serous ovarian cancer.

• Prior progression of disease on a MEK inhibitor (prior binimetinib permitted).

• If patient has previously received binimetinib, they cannot have required dose reduction or discontinuation of binimetinib due to adverse events.

• No prior receipt of a CDK4/6 inhibitor.  

• No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks of the first dose of study therapy.

• No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to the start of study treatment. Patients migrating from Cohort 1 may have received binimetinib within 28 days of registering to Cohort 2

. Cohort 3

• Pancreatic cancer with KRAS/NRAS/HRAS, non-BRAF V600E aMOIs or rare RAF fusions are acceptable. • No prior MEKi and CDK4/6i therapy.

• Progression after at least one line of prior therapy as long as there is no standard therapy available or acceptable to patients that is thought to be of benefit.

• Any number of prior therapies are permitted. • No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks of the first dose of study therapy.

• No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to the start of study treatment. 

Cohort 4

• KRAS/NRAS/HRAS, non-BRAF V600E aMOIs or rare RAF fusions are acceptable.

• No prior MEKi and CDK4/6i therapy and progression after at least one line of prior therapy, as

long as there is no standard therapy available or acceptable to patients that is thought to be of benefit. • Any number of prior therapies are permitted.

• No more than 6 patients with a given tumor type allowed in this cohort. • Any tumor type, except: LGSOC/NSCLC/CRC/pancreatic/melanoma.

• No major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 2 weeks of the first dose of study therapy.

• No prior cancer-directed therapy within 28 days prior to registration. Patients may have received cancer-directed hormonal therapy up to 14 days prior to the start of study treatment. 

3.3.4 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 pregnancy test done ≤ 7 days prior to registration is required. 

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

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton, Livonia) , Sparrow, Geneyes, Hurley

Eligibility Criteria:

3.3.1 Documentation of Disease:

Histologic Documentation: Participants must have histologically confirmed BTC (IHC, EHC or GBC) that is unresectable or recurrent with a confirmed RAS/RAF/MEK/ERK pathway mutation via any CLIA-certified method (tumor or ct-DNA). BRAFV600E mutations are not eligible due to other ongoing/upcoming studies in this disease cohort. 

3.3.2 Measurable disease per RECIST 1.1 as defined in Section 11.0. Of note, in the case when a baseline biopsy is done after scans are obtained, a lesion separate from one that is biopsied needs to be measurable per RECIST 1.1. All radiologic studies must be performed within 28 days prior to randomization.

3.3.3 Prior Treatment

• Progression of disease on gemcitabine based first-line regimen.
• No systemic anti-cancer therapy within 4 weeks of registration to EAY191-A6.
• No prior MEK inhibitor therapy 
• No prior history of treatment with a direct and specific inhibitor of KRAS.
• Patients who only received radio-sensitizing chemotherapy with 5-FU or capecitabine, are eligible but need to have received and failed first-line systemic chemotherapy upon recurrence. Peri-operative systemic 5-FU/capecitabine and/or oxaliplatin, is allowed if it’s been more than 12 months of registration to EAY191-A6.
• No major surgery within 4 weeks (excluding placement of vascular access) of registration to EAY191-A6.
• No minor surgery within 2 weeks of registration to EAY191-A6.
• No palliative radiotherapy within 1 week of registration to EAY191-A6 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health- SJMH (Ann Arbor, Brighton, Chelsea, Canton), Livonia, Genesys, Hurley, Sparrow

Eligibility Criteria:

3.1.1 Patient must fulfill all eligibility criteria outlined in Section 3.1 of and be enrolled on the ComboMATCH Registration Protocol (EAY191) at the time of registration to the EAY191-E4 study. This includes submission of NGS data from one of the MATCH Designated Laboratories for all potential participants prior to treatment protocol assignment. Copy number and allele frequency cutoffs as per the ComboMATCH Registration Protocol.

3.1.2 Patient must be ≥ 18 years of age.

3.1.3 Patient must not have any of the following mutations (as determined by the ComboMATCH Registration Protocol), which are known to confer sensitivity or resistance to nilotinib monotherapy:

3.1.3.1 KIT: W557R, V559D, V559A, L576P, and K642E 3.1.3.2 PDGFR-a: D842V

3.1.4 Patient must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191).

3.1.5 Patient must be willing to provide blood samples for research purposes.

3.1.6 Patient must have had at least one prior line of therapy in the metastatic setting.

3.1.7 Patient must have previously undergone taxane therapy (in the metastatic setting). 

3.1.8 Patient must have an ECOG Performance Status of 0-2.

3.1.9 Patient must not have had platinum-resistant epithelial serous ovarian cancer.

3.1.10 Patient must not have peripheral neuropathy > grade 1.

3.1.11 Patients must not have neuropathy ≥ grade 2 within 14 days of registration/randomization 

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

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton, St. Mary's Livonia, Genesys, Hurley 

Eligibility Criteria: All Patients

3.1.1 Patient must be enrolled on the ComboMATCH Registration Protocol (EAY191) at the time of registration/randomization to the EAY191-E5 study.

3.1.2 Patient must be ≥ 18 years of age.

3.1.3 Patient must have a KRAS G12C alteration as determined by the ComboMATCH screening assessment.

3.1.4 Patient must have disease that can be safely biopsied and agree to a pre-treatment biopsy or have tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191).

3.1.5 Patient must have cytologically/histologically confirmed advanced/metastatic solid tumor.

3.1.6 Patient must have progressed on at least one line of standard of care therapy in the advanced/metastatic setting. NOTE: Patients who have progressed on a prior EGFR inhibitor will meet this criterion.

3.1.7 Patient must have an ECOG Performance Status of ≤ 2 (or Karnofsky Performance Status > 60%). 3.1.8 Patient must have at least one measurable lesion as defined by RECIST in Section 6.1 documented by imaging obtained within 28 days prior to registration/randomization. 

 Eligibility Criteria: Cohort 1 Only

3.2.1 Patient must not have colorectal cancer or non-small cell lung cancer.

3.2.2 Patient must not have been previously treated with a KRAS G12C inhibitor.

3.3 Eligibility Criteria: Cohort 2 Only

3.3.1 Patient must have progressed after treatment at the RP2D of any KRAS G12C inhibitor.

NOTE: Patients on Cohort 1 who experience progression on Regimen 2 (AMG 510 (Sotorasib) alone) may be eligible to enroll on Cohort 2 and receive combination treatment with Panitumumab and AMG 510 (Sotorasib). Patients must meet performance status requirements outlined in Section 3.1.7 and laboratory values outlined in Section 3.1.20 as above and must be begin treatment within 7 days of enrollment. Migration to Cohort 2 must take place within 6 months of progression, with no intervening anti-cancer therapy given.

NOTE: Cohort migration following disease progression is dependent on a slot being available. MATCHBox makes the new treatment assignment following initiation of a Step 2 registration for this treatment trial.

3.3.2 Patient must not have been previously treated with a KRAS G12C inhibitor in combination with an EGFR inhibitor.

***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: SJMH (Canton, Chelsea, Brighton, Ann Arbor,), Livonia, Genesys, Hurley, Sparrow

Eligibility Criteria:

 3.1.1 Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191.

3.1.2 Patients must have RAS pathway mutations as determined by the ComboMATCH screening assessment.

Cohort 1: Patients with histologically confirmed RAS pathway mutant ovarian, primary      peritoneal, or fallopian tube (“ovarian”) cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).

Cohort 2: Patients with histologically confirmed RAS pathway mutant endometrial cancer (activating mutations in KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, or inactivating mutations in NF1).

3.1.3 Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or, if disease cannot be safely biopsied, have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191).

3.1.4 Patients must have progressed after first-line treatment for recurrent or persistent disease.

3.1.5 Patients with ovarian cancer should not be eligible for further platinum-based therapy.

3.1.6 Patients with endometrial cancer must have received or been offered an immune oncology agent (alone or in combination with lenvatinib) unless there are existing contraindications for immune oncology agents or lenvatinib.

3.1.7 Patients may have received unlimited prior therapy.

3.1.8 Patients must have measurable and biopsiable disease. 

3.1.9 Prior therapy must have been completed at least four weeks prior to registration. 3.1.10 Age ≥ 18. 3.1.11 ECOG Performance Status of 0, 1 or 2 see Appendix I) 

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