Patient case: 81-year-old male with Prostate cancer. Genetic variant: PTEN Inactivating. Other conditions: Hypertension, Depression.

Clinical trial: Molecular Profiling-Based Targeted Therapy in Treating Patients With Advanced Solid Tumors

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.

Detailed description: 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 30-60 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. Patients with unacceptable toxicities that have not resolved by day 30 are followed up biweekly until stabilization or resolution.

Eligibility: 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
  -  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 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: 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; 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) 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 who have had prior treatment with any of the other investigational agents or combinations on this protocol are eligible but will not receive the same investigational agent (everolimus or trametinib) or combination (AZD1775/combination or veliparib/temozolomide); instead, patients will receive an investigational agent or combination prospectively identified to work on a different target in their tumor's mutation/aberrant pathway
  -  TREATMENT: Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment 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: Life expectancy > 3 months
  -  TREATMENT: 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 (a+b or a+c or b+c):
  -  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: Breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug
  -  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: 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 ovarian cancer and breast cancer gene (BRCA) mutations must have received specific poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor therapy; if these patients have other mutations of interest, they will be eligible to receive agents based on that mutation
  -  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 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 history of seizures are not eligible to receive veliparib, but patients with a 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 >= 4 weeks will be eligible for other study agents; enzyme inducing anticonvulsants are contraindicated
  -  TREATMENT: Patients who have received prior carboplatin or AZD1775 (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 AZD1775 (MK-1775) would still be eligible to receive other study treatment regimens based on identified genetic mutation(s), other than carboplatin plus AZD1775 (MK-1775)
  -  TREATMENT: Patients who have had prior treatment with any PARP inhibitor in combination with temozolomide are ineligible to receive treatment with veliparib on this study; patients who have received prior temozolomide or PARP inhibitor with or without other chemotherapy/targeted agent aside from temozolomide should not be excluded solely because of receiving prior PARP inhibitor or temozolomide, unless it was in combination; patients who have received temozolomide with a PARP inhibitor in the past are eligible to participate but will not receive veliparib 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 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 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 with current or a history of interstitial lung disease, known severely impaired lung function (spirometry and carbon monoxide diffusing capability test (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: 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 known hypersensitivity reaction to dacarbazine are ineligible to receive temozolomide
  Exclusion Criteria:
  -  TUMOR BIOPSY SEQUENCING: Women who are pregnant or breastfeeding
  -  TUMOR BIOPSY SEQUENCING: Patients who are receiving any other investigational agents
  -  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
  -  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
  -  TREATMENT: Women who are pregnant or breastfeeding
  -  TREATMENT: Patients who are receiving any other investigational agents
  -  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, but patients who have either not had seizures or who have been on stable doses of anti-seizure medicine and had no seizures for 4 weeks will be eligible for other study agents; enzyme-inducing anticonvulsants are contraindicated
  -  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 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 G-tube administration is not allowed
  -  TREATMENT: HIV-positive patients on combination antiretroviral therapy are ineligible
  -  TREATMENT: Eligibility of subjects receiving any medicat

Relevance to patient case: not relevant