*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 TDM1. 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

 **This study is open to SJMH (Ann Arbor site 84029), and Sparrow (site 84049) only. 

6.1 Inclusion Criteria
Subjects are eligible to be included in the study only if all of the following criteria apply:
1. Adults 18 years old or older.
2. Subjects with newly diagnosed epithelial adenocarcinoma of ovarian, fallopian tube or peritoneal origin FIGO Stage III or IV disease.
3. Eligible histologic epithelial cell types: high grade serous adenocarcinoma, high grade endometrioid adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, or adenocarcinoma not otherwise specified (N.O.S.).
4. Completed debulking surgery (either primary debulking surgery or interval debulking surgery at the discretion of the investigator), as defined below:
a. For subjects who undergo primary debulking surgery (Cohort 1 - Primary Surgery):
i. Cycle 1 of chemotherapy ± oregovomab/placebo must be anticipated to occur within 6 weeks after primary debulking surgery, and
ii. The primary debulking surgery is optimal, R1 or R0 (defined as R1, macroscopic no greater than 1 cm in diameter, or R0, microscopic or no evidence of tumor).
b. For subjects who will undergo interval debulking surgery (Cohort 2 ? NACT/Interval Surgery):
i. Subject must have received neoadjuvant treatment with 3 cycles of paclitaxel 175 mg/m2 IV over 3 hours every approximately 3 weeks (21 Days), followed by carboplatin area under the curve (AUC) 5-6
administered intravenously (IV) approximately every 3 weeks (21 Days), and
ii. Cycle 4 of chemotherapy ± oregovomab/placebo must be anticipated to occur within 6 weeks after interval debulking surgery, and
iii. The interval debulking surgery is optimal, R1 or R0 (defined as R1, macroscopic no greater than 1 cm in diameter, or R0, microscopic or no evidence of tumor).
5. Suitable venous access for the study-required procedures.
6. Cohort 1 ? Primary Surgery: Preoperative serum CA-125 levels = 50 U/mL, or in Cohort 2 ? NACT + Interval Surgery: serum CA-125 levels = 50 U/mL prior to first pre-operative chemotherapy.
7. Adequate bone marrow function:
a. Absolute neutrophil count (ANC)  = 1,500/µL
b. Platelets  = 100,000/µL

c. Hemoglobin  = 8.0 g/dL (Note: Blood transfusion is permitted up to 48 hours before first dose of study treatment).
8. Adequate liver function:
a. Bilirubin < 1.5 times upper limit normal (ULN)
b. Lactate Dehydrogenase (LDH), SGOT/AST and SGPT/ALT < 2.5 times ULN
c. Albumin >3.5 g/dL
9. Adequate renal function:
a. Creatinine = 1.5 times ULN
10. ECOG Performance Status of 0 or 1.
11. For women of childbearing potential, must be willing to avoid pregnancy by using a highly effective method of contraception from the first dose of study treatment to 60 days after last dose of study treatment. Adequate contraception is defined in Section 8.2.5.
12. Sign informed consent and authorization permitting release of personal health information.
13. Willingness and ability to complete patient quality of life questionnaires.

6.2 Exclusion Criteria
Subjects are excluded from the study if any of the following criteria apply:
1. BRCA1 or BRCA2 germline gene mutation test result with:
a. Positive, ambiguous or inconclusive result available within 28 days prior to starting study treatment, or
b. Known BRCA1 and BRCA2 somatic mutations, and known positive germline, or
c. Somatic Homologous Recombination Deficiency (HRD) who will receive PARP inhibitor front-line maintenance therapy.
2. Subjects with mucinous adenocarcinoma and low-grade adenocarcinoma.
3. Female subjects who are lactating and breastfeeding, or have a positive serum pregnancy test within 7 days prior to the first dose of study treatment (C1D1 for Cohort 1 or C4D1 for Cohort 2).
4. Any serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the completion of treatment according to this protocol.
5. Active autoimmune disease, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's Disease, multiple sclerosis (MS), or ankylosing spondylitis requiring active disease modifying treatment.
6. Known allergy to murine proteins or hypersensitivity to any of the excipients of the oregovomab, paclitaxel, or carboplatin.
7. Chronically treated with immunosuppressive drugs such as cyclosporine, adrenocorticotropic hormone (ACTH), etc. (see Appendix G).
8. Chronic therapeutic corticosteroid use, defined as > 5 days of prednisone or equivalent, with the exception of inhalers or those on a pre-planned steroid taper. (Note: Premedication with corticosteroids per institutional standard of care is allowed.)

 9. Recognized acquired, hereditary, or congenital immunodeficiency disease, including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia.
10. Clinically significant active infection(s) at the time of screening.
11. Any of the following conditions (on-study testing is not required):
a. Known HIV-infected subjects unless on effective anti-retroviral therapy with an undetectable viral load within 6 months, or
b. Known or suspected hepatitis B if active infection (patients with chronic hepatitis B infection must have an undetectable HBV viral load on suppressive therapy, if indicated; positive surface antibody alone is not an exclusion), or
c. Known or suspected hepatitis C infection which has not been treated and cured unless currently on treatment with an undetectable viral load).
12. Uncontrolled or life-threatening diseases compromising safety evaluation.
13. Diagnosed or treated for another malignancy within 5 years before the first dose, or previously diagnosed with another malignancy and have any evidence of residual disease. Subjects with non-melanoma skin cancer or cervix carcinoma in situ are not excluded if they have undergone complete resection. Synchronous endometrial cancer, but a prior diagnosis of endometrial cancer within 5 years is not excluded if all of the following conditions are met: Stage IA, superficial myometrial invasion, without lymphovascular invasion, grade 3 or not poorly differentiated subtypes including papillary serous, clear cell or other FIGO Grade 3 lesions.
14. Contraindications to the use of pressor agents.
15. Undergone more than one surgical debulking or have not recovered from surgery.
16. Anticipated treatment with any other anti-cancer medications, including bevacizumab, poly (ADP-ribose) polymerase (PARP) inhibitors, or any investigational agent(s) during the study.
17. History or evidence upon physical examination of CNS disease, seizures not controlled with standard medical therapy, or any brain metastases.
18. Any of the following cardiovascular conditions:
a. Acute myocardial infarction within 6 months before the first dose of study treatment.
b. Current history of New York Heart Association (NYHA) Class III or IV heart failure (see Appendix H).
c. Evidence of current uncontrolled cardiovascular conditions including cardiac arrhythmias, angina, pulmonary hypertension, or electrocardiographic clinically significant findings.
19. Unable to read or understand or unable to sign the necessary written consent before starting treatment

-Patients must be candidates for cytoreductive surgery and consent to have their surgical treatment determined by randomization
-Patients must have histologic diagnosis of epithelial ovarian carcinoma, peritoneal primary or fallopian tube carcinoma, which is now recurrent.
-Patients with the following histologic epithelial cell types are eligible: Serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma NOS
-Patients must have had a complete response to front-line platinum-taxane therapy (at least three cycles)
-Patients must have a treatment-free interval without clinical evidence of progressive disease lasting at least 6 months.
-Patients must have clinically evident recurrent disease. 
-GOG PS must be 0-2
-Patients must not have received mor than one previous regimen of chemotherapy
-Patients must not be receiving concurrent immunotherapy or radiotherapy
-Patients who have received prior RT to any portion of the abdominal cavity or pelvis are excluded.
-Patients who have already undergone secondary cytoreduction for recurrence are excluded
-Patients who have received prior chemotherapy for any abdominal or pelvic tumor (other than gyn) are excluded

-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