MPACT Study to Compare Effects of Targeted Drugs on Tumor Gene Variations

Study Overview
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Brief Summary
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This phase II trial studies molecular profiling-based assignment of cancer therapy (MPACT) in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Adavosertib, everolimus, and trametinib are drugs that each target a specific variation in tumors by blocking different proteins needed for cell growth. Veliparib blocks an enzyme that helps repair deoxyribonucleic acid (DNA) damaged by chemotherapy, which may help chemotherapy drugs work better. It is not yet known whether testing patients for variations in their tumor and assigning treatment targeting the variation is more effective than standard non-targeted therapy in treating advanced solid tumors.

Detailed Description
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PRIMARY OBJECTIVE: I. Evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers. OUTLINE: Patients are assigned to 1 of 4 treatment regimens corresponding to one of their mutation/amplification categories. REGIMEN I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide PO once daily (QD) on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. REGIMEN II: Patients receive adavosertib PO BID for 5 doses starting on day 1 and carboplatin intravenously (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018) REGIMEN III: Patients receive everolimus PO every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018) REGIMEN IV: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (No longer an active study drug as of March 2018) After completion of study treatment, patients are followed up for 30 days. Patients with unacceptable toxicities that have not resolved by day 30 are followed up biweekly until stabilization or resolution.

Official Title
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Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors

Conditions
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Advanced Malignant Solid Neoplasm

Intervention / Treatment
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* Drug: Adavosertib
* Drug: Carboplatin
* Drug: Everolimus
* Drug: Temozolomide
* Drug: Trametinib
* Drug: Veliparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TUMOR BIOPSY SEQUENCING: Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy and/or no standard of treatment exists that has been shown to prolong survival TUMOR BIOPSY SEQUENCING: Patient must have tumor amenable to percutaneous or excisional skin biopsy and be willing to undergo a tumor biopsy or biopsy samples (formalin-fixed paraffin-embedded [FFPE] blocks) collected on another study or from a procedure performed due to medical necessity may be acceptable if collected within 6 months prior to registration on molecular profiling-based assignment of cancer therapy (MPACT) and providing that the patient has not received any investigational or targeted treatment since that time, or a report from a Molecular Analysis for Therapy Choice (MATCH) study designated Clinical Laboratory Improvement Act (CLIA) laboratory that a patient has a variant in the genes of interest TUMOR BIOPSY SEQUENCING: Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan TUMOR BIOPSY SEQUENCING: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, denosumab, or similar agents are eligible to participate and may continue this treatment; patients with prostate cancer may continue luteinizing hormone-releasing hormone (LHRH) agonists or antagonists TUMOR BIOPSY SEQUENCING: Karnofsky performance status >= 70% TUMOR BIOPSY SEQUENCING: Life expectancy > 3 months TUMOR BIOPSY SEQUENCING: Absolute neutrophil count >= 1,000/uL (mcL) TUMOR BIOPSY SEQUENCING: Platelets >= 100,000/uL (mcL) TUMOR BIOPSY SEQUENCING: Total bilirubin < 1.5 x institutional upper limit of normal TUMOR BIOPSY SEQUENCING: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal TUMOR BIOPSY SEQUENCING: Creatinine < 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min for patients with creatinine levels >= 1.5 x institutional upper limit of normal TUMOR BIOPSY SEQUENCING: The effects of these targeted agents on the developing human fetus are unknown or anticipated to cause fetal harm based on their mechanism of action; for this reason, women of childbearing potential and men must agree to use highly effective contraception prior to study entry, for the duration of study participation, and for 3 months after completion of study; because there may be a risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug TUMOR BIOPSY SEQUENCING: Patients with history of central nervous system (CNS) metastases who have received treatment and who either have not had seizures or have been on stable doses of anti-seizure medicine and had no seizures for 4 weeks will be eligible; enzyme-inducing anticonvulsants are contraindicated TUMOR BIOPSY SEQUENCING: Ability to understand and the willingness to sign a written informed consent document (subjects with impaired decision-making capacity are not eligible) TREATMENT: Patient must have predefined targeted mutation in tumor biopsy TREATMENT: Patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy or for which no standard therapy exists that has been shown to prolong survival TREATMENT: Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan TREATMENT: Any prior therapy, radiotherapy, or major surgery must have been completed >= 3 weeks (> 6 weeks for nitrosoureas or mitomycin C) or 5 half-lives of the agent (whichever is shorter) prior to enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity; radiofrequency ablation (RFA) of localized lesions should have been performed >= 2 weeks prior to treatment TREATMENT: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment, denosumab, or similar agents are eligible to participate and may continue this treatment; patients with prostate cancer may continue LHRH agonists or antagonists TREATMENT: Karnofsky performance status >= 70% TREATMENT: Absolute neutrophil count >= 1,000/uL (mcL) TREATMENT: Platelets >= 100,000/uL (mcL) TREATMENT: Total bilirubin < 1.5 x institutional upper limit of normal TREATMENT: AST (SGOT)/ALT (SGPT) =< 3 x institutional upper limit of normal TREATMENT: Creatinine < 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min for patients with creatinine levels >= 1.5 x institutional upper limit of normal TREATMENT: Life expectancy > 3 months TREATMENT: The effects of these targeted agents on the developing human fetus are unknown or anticipated to cause fetal harm based on their mechanism of action; for this reason, women of childbearing potential and men must agree to use highly effective contraception (see list below) prior to study entry, for the duration of study participation, and for 3 months after completion of study; Total abstinence: When this is in line with the preferred and usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception) Sterilization: have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate); (for female subjects on the study, the vasectomized male partner should be the sole partner for that subject); use of a combination of any two of the following: Use of oral, injected, implanted or other hormonal methods of contraception Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository In case of use of oral contraception, women should have been stable on the oral agent before taking study treatment Sexually active males must use a condom during intercourse TREATMENT: Because there may be a risk for adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug TREATMENT: Patients with ovarian cancer or metastatic breast cancer and breast cancer gene (BRCA) mutations must have received approved poly (ADP-ribose) polymerase (PARP) inhibitor therapy; these patients are eligible for the veliparib plus temozolomide arm unless the PARP inhibitor was administered with temozolomide TREATMENT: Patients with a history of seizures are not eligible to receive veliparib TREATMENT: Patients who have had prior treatment with any PARP inhibitor in combination with temozolomide are not eligible to receive treatment with veliparib on this study; patients who have received prior temozolomide or PARP inhibitor with or without other chemotherapy/targeted agent should not be excluded TREATMENT: Patients must have >= 10.0 g/dL hemoglobin (Hb) and no blood transfusion in the past 28 days to receive veliparib Exclusion Criteria: TUMOR BIOPSY SEQUENCING: Women who are pregnant or breastfeeding TUMOR BIOPSY SEQUENCING: Patients who are receiving any other investigational agents; patients on other trials will be eligible as long as they are no longer receiving study treatment TUMOR BIOPSY SEQUENCING: Patients with uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e., quantifiable hepatitis B virus [HBV]-DNA and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]) are not eligible to participate; testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated TUMOR BIOPSY SEQUENCING: Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded; subjects with Crohn's disease or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole; tablets or capsules must not be crushed or chewed; nasogastric or gastrostomy tube (G-tube) administration is not allowed TUMOR BIOPSY SEQUENCING: Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic (PK) interactions TUMOR BIOPSY SEQUENCING: Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded; low molecular weight heparin is permitted for prophylactic or therapeutic use TUMOR BIOPSY SEQUENCING: Patients who have previously been treated with the combination of temozolomide plus a PARP inhibitor should not be considered eligible for a biopsy given that these patients would not be eligible for the active veliparib plus temozolomide arm TREATMENT: Women who are pregnant or breastfeeding TREATMENT: Patients who are receiving any other investigational agents; patients on other trials will be eligible as long as they are no longer receiving study treatment TREATMENT: Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients who have a history of seizures are not eligible to receive veliparib TREATMENT: Patients with uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction in the past 6 months, invasive fungal infections, or active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e., quantifiable hepatitis B virus (HBV)-DNA and/or positive hepatitis B surface antibody (HbsAg), quantifiable hepatitis C virus (HCV)-RNA) are not eligible to participate; testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated TREATMENT: Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded; subjects with Crohn's disease or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole; tablets or capsules must not be crushed or chewed; nasogastric or G-tube administration is not allowed TREATMENT: HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions TREATMENT: Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics (i.e., cytochrome P450, family 3, subfamily A, polypeptide 4 [CYP450], P-glycoprotein [PgP]) of any of the study drugs will be determined following review of their cases by the principal investigator (PI); patients on strong and moderate cytochrome P450 system inducers or inhibitors are ineligible; every effort would be made to switch patients off medications that are known substrates of CYP450; if it is medically important for the patient to remain on such medications, these patients can still be eligible to participate based on PI discretion TREATMENT: Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded; low molecular weight heparin is permitted for prophylactic or therapeutic use TREATMENT: Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uteri, or breast from which the patient has been disease free for > 3 years TREATMENT: Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS), or with features suggestive of AML/MDS, or who have had prior allogeneic bone marrow transplant or double umbilical cord blood transplantation, should not receive veliparib due to reports of MDS and leukemia secondary to oncology therapy on Cancer Therapy Evaluation Program (CTEP)-sponsored studies utilizing veliparib

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regimen I (veliparib, temozolomide)<br>Patients receive veliparib by mouth (PO) twice a day (BID) on days 1-7 and temozolomide PO every day (QD) on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Temozolomide<br>* Given by mouth (PO)<br>* Other names: TMZ;Drug: Veliparib<br>* Given by mouth (PO)<br>* Other names: PARP-1 inhibitor ABT-888;|
| Experimental: Regimen II (adavosertib, carboplatin)<br>Patients receive adavosertib by mouth (PO) twice a day (BID) for 5 doses starting on day 1 and carboplatin intravenous (IV) over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: Adavosertib<br>* Given by mouth (PO)<br>* Other names: MK1775;Drug: Carboplatin<br>* Given intravenous (IV)<br>* Other names: Ribocarbo;|
| Experimental: Regimen III (everolimus)<br>Patients receive everolimus by mouth (PO) every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Everolimus<br>* Given by mouth (PO)<br>* Other names: Zortress;|
| Experimental: Regimen IV (trametinib)<br>Patients receive trametinib by mouth (PO) every day (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Trametinib<br>* Given by mouth (PO)<br>* Other names: MEK Inhibitor GSK1120212;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Objective Response | ORR is the proportion of participants with a complete response (CR) or partial response (PR) per the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all tumors. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. | Up to 30 days after completion of study treatment, up to 75 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With 4 Month Progression-free Survival (PFS) | Time from random assignment to progression or death from any cause (whichever comes first). Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST). Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. And the appearance of one or more new lesions is also considered progressions. | 4 months |