Molecular Profiling-Based Targeted Therapy in Treating Patients with Advanced Solid Tumors

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IITreatment18 and over13-C-0105
NCI-2013-01588, 130105, P121047, 9149, NCT01827384

Trial Description

Summary

This randomized pilot phase II trial studies molecular profiling-based targeted therapy in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment. WEE1 inhibitor MK-1775, 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.

Further Study Information

PRIMARY OBJECTIVES:

I. Compare the response rate (complete response [CR] plus partial response [PR]) and 4-month progression-free survival (PFS) for treatment with agents chosen based on the presence of specific mutations in patient tumors with the response rate for treatment with agents chosen from the complementary set of agents not identified to target the mutations of interest.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients are assigned to 1 of 4 treatment regimens corresponding to one of their mutation/amplification categories. Patients may cross over to a second mutation/amplification determined regimen within Arm A, if there is one, upon disease progression.

REGIMEN I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide PO once daily (QD) on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

REGIMEN II: Patients receive WEE1 inhibitor MK-1775 PO BID for 5 doses starting on day 1 and carboplatin intravenously (IV) over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

REGIMEN III: Patients receive everolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

REGIMEN IV: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients are assigned to 1 of the 4 treatment regimens as in Arm A from the complementary set (not corresponding to one of their mutation categories). Patients may cross over to Arm A upon disease progression.

After completion of study treatment, patients are followed up for 30 days.

Eligibility Criteria

Inclusion Criteria:

TREATMENT: For patients on everolimus, fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x upper limit of normal (ULN); NOTE: in case one or both of these thresholds are exceeded, the patient can receive everolimus on study only after initiation of appropriate lipid lowering medication with follow up documentation of values below the above cut-off

TREATMENT: Patients with current or a history of interstitial lung disease, known severely impaired lung function (spirometry and DLCO 50% or less of normal and oxygen [O2] saturation 88% or less at rest on room air) or non-infectious pneumonitis will not be assigned treatment with everolimus or trametinib DMSO; symptoms should have resolved and course of antibiotics been completed for patients with a history of infectious pneumonitis to be eligible

TREATMENT: Patients who have received prior mitogen-activated protein kinase kinase (MEK) inhibitors would not be eligible to receive trametinib DMSO on study; if these patients have mutations of interest in pathways other than the rat sarcoma (RAS) pathway, they will be eligible to receive agents based on that mutation

TREATMENT: Patients who have received prior everolimus or other mechanistic target of rapamycin (mTOR) inhibitors or those with known intolerance or hypersensitivity to other rapamycin analogs (e.g., sirolimus, temsirolimus) would not be eligible to receive everolimus on study; if these patients have mutations of interest in pathways other than the phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (pI3K) pathway, they will be eligible to receive agents based on that mutation

TREATMENT: Patients who have had prior treatment with any poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (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

TREATMENT: Patients who have received prior carboplatin or MK-1775 (WEE1 inhibitor 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

TREATMENT: Patients with a history of seizures are not eligible to receive ABT-888; patients with brain metastatic disease must have remained stable for > 3 months and be off steroid treatment to be eligible to receive ABT-888

TREATMENT: Patients with a history or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) or predisposing factors to RVO or RPED (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 RPED includes evidence of new optic disc cupping or new visual field defects, or intraocular pressure > 21 mm Hg

TREATMENT: Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib dimethyl sulfoxide (DMSO), its excipients, or DMSO, are ineligible to receive treatment with trametinib DMSO

TREATMENT: Patients who have poorly controlled diabetes (defined as fasting blood glucose of > 160 mg/dL [Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2] and hemoglobin A1c [HgA1c] > 8%) are ineligible to receive treatment with everolimus on study

TREATMENT: Patients with non-small cell lung cancer (NSCLC) must have previously been tested for the presence of epidermal growth factor receptor (EGFR) mutations, and, if detected, should have received and progressed on EGFR tyrosine kinase inhibitor (TKI) therapy

TREATMENT: Patients with melanoma and known v-raf murine sarcoma viral oncogene homolog B (BRAF) V600E mutations must have received and progressed on specific BRAF inhibitor therapy

TREATMENT: 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; breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug

TREATMENT: International normalized ratio (INR) < 2

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: AST (SGOT)/ALT (SGPT) =< 3 x institutional upper limit of normal

TREATMENT: Total bilirubin < 1.5 x institutional upper limit of normal

TREATMENT: Platelets >= 100,000/uL (mcL)

TREATMENT: Absolute neutrophil count >= 1,500/uL (mcL)

TREATMENT: Life expectancy > 3 months

TREATMENT: Karnofsky performance status >= 70%

TREATMENT: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment are eligible to participate and may continue this treatment

TREATMENT: 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

TREATMENT: Any prior therapy, radiotherapy, or major surgery must have been completed >= 3 weeks (> 6 weeks for nitrosoureas or mitomycin C) 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 enrollment

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: 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: Patient must have predefined targeted mutation in tumor biopsy

TUMOR BIOPSY SEQUENCING: Ability to understand and the willingness to sign a written informed consent document

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 2 weeks will be eligible; enzyme-inducing anticonvulsants are contraindicated

TUMOR BIOPSY SEQUENCING: 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; breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug

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: 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: Total bilirubin < 1.5 x institutional upper limit of normal

TUMOR BIOPSY SEQUENCING: Platelets >= 100,000/uL (mcL)

TUMOR BIOPSY SEQUENCING: Life expectancy > 3 months

TUMOR BIOPSY SEQUENCING: Karnofsky performance status >= 70%

TUMOR BIOPSY SEQUENCING: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment are eligible to participate and may continue this treatment

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 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

TREATMENT: Patients with ovarian or breast cancer and breast cancer (BRCA) mutations will not receive ABT-888 (veliparib) on study; if these patients have other mutations of interest, they will be eligible to receive agents based on that mutation

TREATMENT: Hemoglobin (Hgb) >= 9 g/dL

TUMOR BIOPSY SEQUENCING: Partial thromboplastin time (PTT) =< 40 seconds unless due to lupus coagulant

TUMOR BIOPSY SEQUENCING: Absolute neutrophil count >= 1,000/uL (mcL)

TUMOR BIOPSY SEQUENCING: Patient must have tumor amenable to percutaneous biopsy and be willing to undergo a tumor biopsy

Exclusion Criteria:

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 a history or current evidence/risk of RVO or RPED or predisposing factors to RVO or RPED (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 RPED includes evidence of new optic disc cupping or new visual field defects, or intraocular pressure > 21 mm Hg

TREATMENT: Patients who have received live attenuated vaccines within 1 week of the start are ineligible to receive everolimus

TREATMENT: Patients requiring chronic treatment with corticosteroids or other immunosuppressive agents are ineligible to receive everolimus (topical or inhaled corticosteroids are allowed)

TREATMENT: 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

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: 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 CYP 3A4; 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; CYP3A4-sensitive substrates or substrates of this enzyme with a narrow therapeutic index will not be administered concomitantly

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 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

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 HBV-DNA and/or positive HbsAg, quantifiable 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 active brain metastases or carcinomatous meningitis are excluded from this clinical trial; patients whose brain metastatic disease status has remained stable for > 3 months and are off steroid treatment are eligible to receive ABT-888; patients whose brain metastatic disease status has remained stable for >= 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

TREATMENT: Patients who are receiving any other investigational agents

TREATMENT: Women who are pregnant or breastfeeding

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: Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

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 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 gastrostomy tube (G-tube) administration is not allowed

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 who are receiving any other investigational agents

TUMOR BIOPSY SEQUENCING: Women who are pregnant or breastfeeding

TREATMENT: Patients who have poorly controlled diabetes (defined as fasting blood glucose of > 160 mg/dL (CTCAE grade >= 2) and HgA1c > 8% are ineligible to receive treatment with everolimus on study; patients with fasting blood glucose > 160 mg/dL may be eligible if the HgA1c < 8%, per PI discretion

TREATMENT: HIV-positive patients on combination antiretroviral therapy are ineligible

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
A P Chen, Principal Investigator

Trial Sites

U.S.A.

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

A P Chen
Ph: 301-496-4291
Email: chenali@mail.nih.gov

A P Chen
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01827384

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.