Clinical Trials /

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

NCT01827384

Description:

This 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. 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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Molecular Profiling-Based Targeted Therapy in Treating Patients With Advanced Solid Tumors
  • Official Title: Molecular Profiling-Based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-01588
  • SECONDARY ID: NCI-2013-01588
  • SECONDARY ID: MPACT
  • SECONDARY ID: 130105
  • SECONDARY ID: P121047
  • SECONDARY ID: 9149
  • SECONDARY ID: 9149
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT01827384

Conditions

  • Advanced Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
AdavosertibAZD-1775, AZD1775, MK-1775, MK1775Regimen II (adavosertib, carboplatin)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboRegimen II (adavosertib, carboplatin)
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressRegimen III (everolimus)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, TemomedacRegimen I (veliparib, temozolomide)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistRegimen IV (trametinib)
VeliparibABT-888, PARP-1 inhibitor ABT-888Regimen I (veliparib, temozolomide)

Purpose

This 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. 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

      PRIMARY OBJECTIVES:

      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.

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

      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.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Regimen I (veliparib, temozolomide)ExperimentalPatients receive veliparib PO BID on days 1-7 and temozolomide PO QD on days 1-5. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Temozolomide
  • Veliparib
Regimen II (adavosertib, carboplatin)ExperimentalPatients receive adavosertib PO BID for 5 doses starting on day 1 and carboplatin IV over 30-60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Adavosertib
  • Carboplatin
Regimen III (everolimus)ExperimentalPatients receive everolimus PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Everolimus
Regimen IV (trametinib)ExperimentalPatients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Trametinib

Eligibility 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

          -  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 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 BRCA mutations
             must have received approved 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 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 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
             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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description:The comparison of response rates will have 88% power to detect an over-all difference of 20% versus (vs.) 5% objective response, by means of the chi-square test, conducted at the 1-sided .04 significance level.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:4 months
Safety Issue:
Description:The comparison of PFS will have 90% power to detect an over-all increase of 80% in median PFS (for example, 3.6 vs. 2 months), by means of the logrank test, conducted at the 1-sided .01 significance level, with at least 165 PFS events observed.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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