*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***

*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, Chelsea, Canton), Livonia, Genesys, Hurley

Eligibility Criteria:

3.2 Eligibility Criteria

A patient cannot be considered eligible for this study unless ALL of the following conditions are met. 3.2.1 Patients must be enrolled on the ComboMATCH Master Registration Trial EAY191.

3.2.2 Documentation of Disease Patients must have a HER2 amplified solid tumor except breast cancer. Patient’s cancer must have HER2 amplification as defined with ≥ 7 copies by NGS testing. Patients must have recurrent or persistent disease. No known evidence of RB1 loss or deletion including copy number loss or deleterious mutation.

3.2.3 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).

3.2.4 Definition of Measurable Disease as defined by RECIST (see Section 12.1 for criteria) Patients must have measurable disease based on RECIST 1.1. A second measurable lesion outside of the biopsiable lesion is required. Patients with treated brain metastases are eligible if follow up brain imaging after CNS directed therapy shows no evidence of progression for 3 months or more and patient is not on steroids and is asymptomatic. No known leptomeningeal disease.  

3.2.5 Prior Treatment Patients may have received up to 5 prior lines of systemic therapy. Prior therapy with trastuzumab or pertuzumab, either alone or in combination, is allowed. One prior line of anti-HER2 therapy is allowed except tyrosine kinase inhibitors (TKI) such as neratinib or tucatinib or antibody drug conjugates (ADC) such as DS8201a or T\u0002DM1. No prior therapy with CDK4/6 inhibition. No cancer directed therapy within 3 weeks prior to registration. For oral therapy, the washout can be reduced to greater than or equal to 5 half lives of the drug.

3.2.6 Age ≥ 18

3.2.7 ECOG Performance Status of ≤2 (see Appendix I).

3.2.8 Not Pregnant and Not Nursing

3.2.9 Required Organ Function Adequate hematologic function defined as follows: • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

• Platelets ≥ 100,000 cells/mm3

• Hemoglobin ≥9 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥9 g/dl is acceptable). 

Adequate renal function defined as follows:

• Creatinine clearance (CrCL) of ≥30 mL/min by the Cockcroft-Gault formula 

Adequate hepatic function defined as follows:

• Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert’s disease who have bilirubin level ≤ 3 x institutional ULN may be enrolled).

• AST and ALT ≤ 3 x institutional ULN. Adequate cardiac function defined as follows:

• 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 (see Appendix II.)  

3.2.10 Comorbid Conditions

• No active infection requiring parenteral antibiotics

• No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not diverted), gastrointestinal perforation, GI obstruction, and/or need for drainage nasogastric or gastrostomy tube

• No current evidence of malabsorption or chronic diarrhea or any other significant gastro-intestinal disease (e.g gastrectomy, ileal bypass, Crohn’s disease, gastroparesis), associated with moderate to severe diarrhea (grade 2 or more) or inability to tolerate oral therapy

• No lung disease causing dyspnea at rest

• No interstitial lung disease with ongoing signs and symptoms at the time of registration

3.2.11 Allergies

No history of allergic reaction to the study agents, compound of similar chemical or biologic composition of the study agents or any of their excipients  

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

Eligibility Criteria:

General ComboMATCH EAY191 Registration Criteria

a. Participants must be enrolled on the ComboMATCH Master Registration Trial EAY191.

b. Participants must have an activating AKT mutation (a known mutation in AKT1, AKT2, or AKT3, a single nucleotide variant, insertion, or deletion) as determined by the ComboMATCH screening assessment.

c. Participants must not have an activating KRAS, NRAS, HRAS, or BRAF mutation (a single nucleotide variant, insertion, or deletion) as determined by the ComboMATCH screening assessment. d. Participants must have disease that can be safely biopsied and agree to a pretreatment biopsy or have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH Registration Trial (EAY191).

Disease Related Criteria

a. Participants must have a histologically confirmed non-breast solid malignancy.

b. Participants must have locally advanced, unresectable, or metastatic disease in the opinion of the treating investigator.

c. Participants must have measurable disease (Section 10.1) documented by CT or MRI.

d. Participants with known brain metastases must have a CT/MRI scan to evaluate for CNS disease and show no evidence of progression within 42 days prior to registration.

e. Participants must have completed any CNS-directed therapy and/or local therapy for spinal cord compression at least 28 days prior to registration.

f. Participants must not have spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days prior to registration, AND (2) participant has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to registration.

g. Participants must not have leptomeningeal disease.

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

*Only available to SJMH (A2, Brighton, Canton, Chelsea), St. Mary's Saginaw, Sparrow, and Genesys Hurley.

-Intention to administer doxorubicin/cyclophosphamide followed by paclitaxel
-Must be female
-ECOG PS must be 0-1
-Diagnosis of invasive adenocarcinoma of the breast made by core needle biopsy
-Primary tumor must be palpable and measure at least 2.0cm on physical exam
-Regional nodes can be cN0, cN1, or cN2a
-Grade II or III tumor
-Patients are eligible with either hormone receptor positive or negative tumors
-Must be HER2-negative
-Must NOT have T4 tumor, including inflammatory breast cancer
-Must NOT have excisional bx or lumpectomy or surgical axillary staging procedure performed prior to chemo. Pre-neoadjuvant therapy sentinel node biopsy is NOT allowed. (FNA is permitted).
-Must not have metastatic disease
-Must not have synchronous bilateral invasive breast cancer