NCI-MPACT: Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01827384
First received: April 4, 2013
Last updated: August 2, 2014
Last verified: September 2013
  Purpose

Background:

- Variations in the genes in some tumors play an important role in how a cancer grows and develops. Looking at these variations and finding drugs that target them is one possible way to treat cancer. However, researchers do not yet know if this way works better than standard cancer treatments. Researchers are interested in studying people who have tumor gene variations in different types of cancer cells. They want to see if these people benefit more from being treated with a drug that specifically targets that variation than from being treated with drugs that do not. To do so, they will look at the genes from people with different sorts of cancers. Based on this analysis, they will offer treatments based on the specific gene variations found on the tumor cells.

Objectives:

- To see if choosing specific treatment options for tumor gene variations is more safe and effective than standard cancer treatments.

Eligibility:

- Individuals at least 18 years of age who have advanced solid tumors that have not responded to standard treatments.

Design:

  • This study will try four different drugs or drug combinations for cancer treatment. Some of these treatments target specific tumor gene variations, while others do not. However, all drugs are intended to be used as possible cancer treatment options.
  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and heart and lung function tests will also be performed.
  • Participants will provide a tumor tissue sample for study. This sample will be used to determine possible tumor gene variations.
  • Participants will be divided into groups based on their tumor gene variation. Within these groups, they will be further divided into two possible study arms. One arm will receive a drug or drug combination designed to target the tumor gene variation. The other arm will receive a drug or drug combination that is not designed to target the variation.
  • Participants will receive their study drugs according to the standard dosing schedule for their treatment. Treatment will be monitored with frequent blood tests and imaging studies. If the cancer gets worse while a participant is on a study drug not designed to work on the tumor s gene variation, the study doctors may change the drug to one thought to work on that variation.
  • Participants will have frequent follow-up visits to monitor the outcome of the treatment. These visits may include additional tumor biopsies.

Condition Intervention Phase
Neoplasms
Drug: Temozolomide
Drug: Everolimus
Drug: Carboplatin
Drug: Trametinib DMSO
Drug: ABT-888
Drug: MK-1775
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind
Primary Purpose: Treatment
Official Title: Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Compare response rate and/or 4-month PFS for agents chosen based on presence of specific tumor mutations/amplifications with response rate for agents randomly chosen from complementary set of agents not identified to target mutations of interest... [ Time Frame: 1.5 - 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 700
Study Start Date: March 2013
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
Receive an agent from the set corresponding to one of their mutation/amplication categories.
Drug: Temozolomide
N/A
Drug: Everolimus
N/A
Drug: Carboplatin
N/A
Drug: Trametinib DMSO
N/A
Drug: ABT-888
N/A
Drug: MK-1775
N/A
Active Comparator: Arm B
Receive an agent chosen, by physician choice, from the complementary set (not corresponding to one of their mutation/amplication categories).
Drug: Temozolomide
N/A
Drug: Everolimus
N/A
Drug: Carboplatin
N/A
Drug: Trametinib DMSO
N/A
Drug: ABT-888
N/A
Drug: MK-1775
N/A

Detailed Description:

Background:

-Targeted therapy based on identifying underlying genetic aberrations within the tumor is the goal of personalized medicine. This pilot trial aims to establish whether advanced cancer patients who have no treatment options with proven benefit, and with tumor mutations/amplifications in one of 3 genetic pathways (DNA repair, PI3K, or RAS/RAF) are more likely to derive clinical benefit if treated with agents targeting that pathway than if treated with agents that do not. Each patient will be randomly assigned to receive the recommended Phase II dose of either a study drug identified to work on their tumor s mutation/aberrant pathway, or an agent from the complementary set not identified to work on the mutations/amplifications of interest.

Objectives:

-Compare the response rate (CR+PR) and/or 4-month PFS for treatment with agents chosen based on the presence of specific mutations/amplifications in patient tumors with the response rate for treatment with agents randomly chosen from the complementary set of agents not identified to work on the mutations/amplifications of interest.

Eligibility:

  • Adult patients with histologically documented solid tumors whose disease has progressed following at least one line of standard therapy and/or for which no standard treatment is available that has been shown to improve survival.
  • Tumor amenable to percutaneous biopsy, and willingness to undergo tumor biopsy.

Study Design:

  • Patients enrolled on study will have a tumor biopsy sequenced in a CLIA-certified lab for specific mutations/amplifications of interest: DNA repair pathways, PI3K pathway, or RAS/RAF/MEK pathway. If such mutations are not detected, the patient will be taken off study.

    • Patients with melanoma and known BRAF V600E mutations need to have received and progressed on specific BRAF inhibitor therapy.
    • Patients with ovarian or breast cancer and BRCA mutations will not receive ABT-888 on study for the treatment of BRCA-positive tumors. They will only be eligible to receive any of the study treatments if they have other mutations of interest.
    • Patients with NSCLC should have been previously tested for the presence of EGFR and ALK mutations, and, if detected, should have received and progressed on EGFR or ALK TKI therapy.
  • Patients in whom a mutation of interest is detected will be randomized 2:1 into Arms A or B: Arm A will receive an agent prospectively identified to target that mutation/pathway; Arm B will receive an agent from the complementary set (not prospectively identified to target one of their mutations). Patients in Arm B will be allowed to cross over at the time of disease progression to a treatment regimen based on their mutational analysis.
  • Targeted drugs will be administered at recommended Phase II doses and schedules: (1) ABT-888 (PARP inhibitor) with temozolomide for defects in the DNA repair pathway; (2) MK-1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathway; (3) Everolimus (mTOR inhibitor) for mutations in the PI3K pathway; or (4) Trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway.
  • Given the relative frequencies of the mutations, approximately 700 patients will need to be enrolled to acquire 180 evaluable patients; the initial feasibility part of the trial will be conducted in the first 60 evaluable patients, requiring enrollment of 100-150 patients.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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.
  • Patient must have tumor amenable to percutaneous biopsy and be willing to undergo a tumor biopsy.
  • 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 greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan.
  • Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment are eligible to participate and may continue this treatment.
  • Age greater than or equal 18 years. Children are excluded from this study, but may be eligible for future pediatric trials.
  • Karnofsky performance status greater than or equal 70
  • Life expectancy greater thatn 3 months.
  • Patients must have adequate organ and marrow function as defined below:

    • absolute neutrophil count greater than or equal to 1,500 per microliters (mcL)
    • platelets greater than or equal to 100,000 per microliters (mcL)
    • total bilirubin less than 1.5 times institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
    • creatinine less than 1.5 times institutional upper limit of normal

OR

  • creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels greater than or equal to 1.5 times institutional upper limit of normal.
  • PTT less than or equal to 40 seconds unless due to lupus coagulant

    • The effects of these targeted agents on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate 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.
    • Patients with history of 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 2 weeks will be eligible. Enzyme-inducing anticonvulsants are contraindicated.
    • Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA: Tumor Biopsy Sequencing

  • Women who are pregnant or breastfeeding.
  • Patients who are receiving any other investigational agents.
  • 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, or left ventricular ejection fraction (LVEF) less than or equal to the institutional lower limit of normal (by ECHO or MUGA), invasive fungal infections, or active hepatitis B infection are not eligible to participate. Testing for hepatitis B or other infections

for eligibility will be performed only if clinically indicated.

  • Patients who have had prior treatment with any PARP inhibitor are ineligible to receive treatment with a PARP inhibitor on this study.
  • Patients who have received prior temozolomide should not be excluded solely because of receiving prior temozolomide, unless it was in combination with a PARP inhibitor. Such patients will not be offered ABT-888 with temozolomide, but are eligible to receive other treatment regimens on study based on identified genetic mutations.
  • 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 ulcerative colitis, inflammatory bowel 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.
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.
  • Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic use. Only patients who meet the screening criteria and have a tumor biopsy determined to have one of the specific mutations/amplifications of interest will be eligible to participate in the treatment part of this protocol.

INCLUSION CRITERIA: Treatment

  • Patient must have predefined targeted mutation in tumor biopsy.
  • 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.
  • 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 greater than or equal to 20 mm with conventional techniques or as greater than or equal 10 mm with spiral CT scan.
  • Any prior therapy, radiotherapy, or major surgery must have been completed greater than or equal 3 weeks (greater than 6 weeks for nitrosoureas or mitomycin C) prior to enrollment on protocol, and the participant must have recovered to eligibility levels from prior toxicity. RFA of localized lesions should have been performed greater than or equal 2 weeks prior to enrollment.
  • Patients who have had prior treatment with any of the other investigational agents on this protocol are eligible but will not receive the same investigational agent; instead, patients will receive an investigational agent prospectively identified to work on a different target in their tumor s mutation/aberrant pathway.
  • Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment are eligible to participate and may continue this treatment.
  • Age greater than or equal 18 years. Because no dosing or adverse event data are currently available on the use of study investigational agents in patients less than 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
  • Karnofsky performance status greater than or equal 70%.
  • Life expectancy greater than 3 months.
  • Patients must have adequate organ and marrow function as defined below:

    • absolute neutrophil count greater than or equal 1,500 per microliters (mcL)
    • platelets greater than or equal 100,000 per microliters (mcL)
    • total bilirubin less than 1.5 times institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of normal
    • creatinine less than 1.5 times institutional upper limit of normal

OR

  • creatinine clearance greater than or equal 60 mL/min for patients with creatinine levels greater than or equal 1.5 times institutional upper limit of normal.

    • The effects of these targeted agents on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (abstinence; female use of hormonal methods, or barrier methods of birth control; male use of a condom) 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.
    • Patients with melanoma and known BRAF V600E mutations must have received and progressed on specific BRAF inhibitor therapy.
    • Patients with NSCLC must have previously been tested for the presence of EGFR mutations, and, if detected, should have received and progressed on EGFR tyrosine kinase inhibitor (TKI) therapy.
    • Patients with ovarian or breast cancer and BRCA mutations will not receive ABT- 888 on study. There is already some evidence of clinical benefit of treating patients with known BRCA-positive tumors with PARP inhibitors. Such patients can pursue therapy on trials specifically testing PARP inhibitors in BRCApositive patients with advanced tumors. If these patients have other mutations of interest as defined in the protocol, they will be eligible to receive agents based on that mutation.
    • Patients who have poorly controlled diabetes (defined as fasting blood glucose of greater than 160 mg/dL (CTCAE Grade greater than or equal to 2) and HgA1c greater than 8%) are ineligible to receive treatment with everolimus on study.
    • Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to Trametinib DMSO, its excipients, or DMSO, are ineligible to receive treatment with Trametinib DMSO.
    • Patients with a history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes), are ineligible to receive treatment with Trametinib DMSO. Visible retinal pathology (as assessed by ophthalmic exam) that is considered a risk factor for RVO or CSR includes evidence of new optic disc cupping or new visual field defects, or intraocular pressure greater than 21 mm Hg.
    • Patients with a history of seizures are not eligible to receive ABT-888. Patients with brain metastatic disease must have remained stable for greater than 3 months and be off steroid treatment to be eligible to receive ABT-888.
    • Patients who have received prior carboplatin or MK-1775 would not be excluded unless the two drugs were administered in combination. Patients who have received prior carboplatin in combination with MK 1775 would still be eligible to receive other study treatment regimens based on identified genetic mutation(s), other than carboplatin plus MK-1775.
    • Patients who have had prior treatment with any PARP inhibitor are ineligible to receive treatment with a PARP inhibitor on this study. Patients who have received prior temozolomide should not be excluded solely because of receiving prior temozolomide, unless it was in combination with a PARP inhibitor. Patients who have received temozolomide with a PARP inhibitor in the past are eligible to participate but will not receive ABT-888 with temozolomide on study. Such patients are eligible to receive other treatment regimens on study based on identified genetic mutations.
    • Patients who have received prior everolimus or other mTOR inhibitors would not be eligible to receive everolimus on study. If these patients have mutations of interest in pathways other than the pI3K pathway as defined in the protocol, they will be eligible to receive agents based on that mutation.
    • Patients who have received prior MEK inhibitors would not be eligible to receive trametinib DMSO on study. If these patients have mutations of interest in pathways other than the RAS pathway as defined in the protocol, they will be eligible to receive agents based on that mutation.
    • Patients with a history of interstitial lung disease or pneumonitis will not be assigned treatment with everolimus.

EXCLUSION CRITERIA: Treatment

  • Women who are pregnant or breastfeeding.
  • Patients who are receiving any other investigational agents.
  • Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than 3 months and are off steroid treatment are eligible to receive ABT-888; patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of the brain metastases are eligible for other study agents. Patients who have a history of seizures are not eligible to receive ABT- 888, but patients who have either not had seizures or who have been on stable doses of anti-seizure medicine and had no seizures for 1 month will be eligible for other study agents. Enzyme-inducing anticonvulsants are contraindicated.
  • 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, or left ventricular ejection fraction (LVEF) less than or equal to the institutional lower limit of normal (by ECHO or MUGA), invasive fungal infections, or active hepatitis B infection are not eligible to participate. Testing for hepatitis B or other infections for eligibility will be performed only if clinically indicated.
  • 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 ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow tablets or capsules whole. T...
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01827384

Contacts
Contact: Ramya Antony (301) 594-4949 parthasarathyr@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01827384     History of Changes
Other Study ID Numbers: 130105, 13-C-0105
Study First Received: April 4, 2013
Last Updated: August 2, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Targeted Therapy
Genetic Sequencing
Advanced Cancer
Pharmacodynamics
Tumor Mutations

Additional relevant MeSH terms:
Neoplasms
Everolimus
Sirolimus
Temozolomide
Trametinib
Carboplatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on August 28, 2014