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 complete loss of cytoplasmic and nuclear PTEN by immunohistochemistry as determined via the MATCH Master Protocol and described in Appendix I. Patients can have any PTEN mutation or deletion status, but MUST have PTEN loss by IHC.
-Patients must not have co-existing aberrations in the MAPK or PI3K/MTOR pathways as determined by the MATCH screening assessment in NRAS, HRAS, KRAS, BRAF, PIK3CA, AKT or mTOR.
-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 (e.g. complete left bundle branch block, third degree heart block).
-Patients must not have known hypersensitivity to copanlisib or compounds of similar chemical or biologic composition.
-Patients must not have had prior treatment with copanlisib or other PI3K inhibitors, AKT inhibitors or mTOR inhibitors.
-Patients must not be on strong inhibitors or inducers of CYP3A4 within two weeks prior to start of study treatment and for the duration of study treatment.
-Patients must not have uncontrolled hypertension defined as SBP greater than 160 mmHg or diastolic BP greater than 100 mmHg or use of more than 2 anti-hypertensive medications.

-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 mutations in the PTEN

gene with 1% or more expression of PTEN by IHC as determined via the MATCH Master Protocol and as described in Appendix I.
-Patients must not have co-existing aberrations in the MAPK or PI3K/MTOR pathways as determined by the MATCH screening assessment in NRAS, HRAS, KRAS, BRAF, PIK3CA, AKT or mTOR.

-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 hypersensitivity to copanlisib or compounds of similar chemical or biologic composition.

-Patients must not require prior treatment with copanlisib or other PI3K inhibitors, AKT inhibitors or mTOR inhibitors.

Patients must not be on strong inhibitors or inducers of CYP3A4 within two weeks prior to start of study treatment and for the duration of study treatment.

-Patients must not be on anti-arrhythmic therapy other than digoxin or beta-blockers.

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 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**