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Methoxyamine, Cisplatin, and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors or Mesothelioma That Cannot Be Removed by Surgery or Mesothelioma That Is Refractory to Pemetrexed Disodium and Cisplatin or Carboplatin

NCT02535312

Description:

This phase I/II trial studies the side effects and the best dose of methoxyamine when given together with cisplatin and pemetrexed disodium and to see how well it works in treating patients with solid tumors or mesothelioma that have spread to other places in the body and usually cannot be cured or controlled with standard treatment (advanced), or mesothelioma that does not respond to pemetrexed disodium and cisplatin or carboplatin (refractory). Methoxyamine may shrink the tumor and may also help cisplatin and pemetrexed disodium work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as cisplatin and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving methoxyamine together with cisplatin and pemetrexed disodium may be a better treatment for solid tumors or mesothelioma than methoxyamine and pemetrexed disodium.

Related Conditions:
  • Malignant Solid Tumor
  • Peritoneal Mesothelioma
  • Pleural Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Methoxyamine, Cisplatin, and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors or Mesothelioma That Cannot Be Removed by Surgery or Mesothelioma That Is Refractory to Pemetrexed Disodium and Cisplatin or Carboplatin
  • Official Title: Phase I Study of TRC102 in Combination With Cisplatin and Pemetrexed in Patients With Advanced Solid Tumors, With Expansion Cohort in Mesothelioma / Phase II Study of TRC102 With Pemetrexed in Patients Refractory to Pemetrexed and Cisplatin or Carboplatin

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-00127
  • SECONDARY ID: NCI-2015-00127
  • SECONDARY ID: PHI-76
  • SECONDARY ID: 9837
  • SECONDARY ID: 9837
  • SECONDARY ID: UM1CA186689
  • SECONDARY ID: UM1CA186705
  • SECONDARY ID: UM1CA186717
  • SECONDARY ID: ZIABC011078
  • NCT ID: NCT02535312

Conditions

  • Advanced Malignant Solid Neoplasm
  • Advanced Peritoneal Malignant Mesothelioma
  • Advanced Pleural Malignant Mesothelioma
  • Recurrent Peritoneal Malignant Mesothelioma
  • Recurrent Pleural Malignant Mesothelioma
  • Stage III Non-Small Cell Lung Cancer AJCC v7
  • Stage III Ovarian Cancer AJCC v6 and v7
  • Stage III Pleural Malignant Mesothelioma AJCC v7
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIA Ovarian Cancer AJCC v6 and v7
  • Stage IIIB Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIB Ovarian Cancer AJCC v6 and v7
  • Stage IIIC Ovarian Cancer AJCC v6 and v7
  • Stage IV Non-Small Cell Lung Cancer AJCC v7
  • Stage IV Ovarian Cancer AJCC v6 and v7
  • Stage IV Pleural Malignant Mesothelioma AJCC v7
  • Thymoma
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm A (methoxyamine, pemetrexed disodium, cisplatin)
MethoxyamineTRC102Arm A (methoxyamine, pemetrexed disodium, cisplatin)
Pemetrexed DisodiumAlimta, LY231514, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium SaltArm A (methoxyamine, pemetrexed disodium, cisplatin)

Purpose

This phase I/II trial studies the side effects and the best dose of methoxyamine when given together with cisplatin and pemetrexed disodium and to see how well it works in treating patients with solid tumors or mesothelioma that have spread to other places in the body and usually cannot be cured or controlled with standard treatment (advanced), or mesothelioma that does not respond to pemetrexed disodium and cisplatin or carboplatin (refractory). Methoxyamine may shrink the tumor and may also help cisplatin and pemetrexed disodium work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as cisplatin and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving methoxyamine together with cisplatin and pemetrexed disodium may be a better treatment for solid tumors or mesothelioma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) for
      the combination of TRC102 (methoxyamine) with pemetrexed (pemetrexed disodium) and cisplatin
      in patients with advanced solid tumors. (Arm A) II. To describe the toxicities of TRC102
      combined with pemetrexed and cisplatin at each dose studied. (Arm A) III. To assess
      preliminary safety and activity in an expansion cohort of chemotherapy-naive advanced
      unresectable malignant mesothelioma patients. (Arm A) IV. To describe responses to the drug
      combination at each dose level. (Arm A) V. To detect activity of the combination of TRC102
      and pemetrexed, as evidenced by tumor response in patients with advanced malignant
      mesothelioma previously treated with pemetrexed and cisplatin. (Arm B)

      SECONDARY OBJECTIVES:

      I. To describe pharmacokinetic parameters of TRC102 given concurrent with pemetrexed and
      cisplatin.

      II. To evaluate the pharmacodynamic parameters of TRC102 given concurrently with pemetrexed
      and cisplatin.

      III. To explore the feasibility of establishing pleural and peritoneal effluent-derived cell
      lines and to evaluate the response of cultured pleural and peritoneal mesothelioma cells to
      cisplatin, pemetrexed, and TRC102.

      IV. To document all objective clinical responses to TRC102 in combination with pemetrexed and
      cisplatin.

      OUTLINE: This is a phase I, dose-escalation study of methoxyamine followed by a phase II
      study. Patients are assigned to 1 of 2 treatment arms.

      ARM A: Patients receive methoxyamine orally (PO) on days 1-4, pemetrexed disodium
      intravenously (IV) over 10 minutes, and cisplatin IV over 30-60 minutes on day 1. Treatment
      repeats every 21 days for up to 6 courses in the absence of disease progression or
      unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond
      course 6 if the patient continues to benefit from treatment at the discretion of the treating
      physician.

      ARM B: Patients receive methoxyamine PO on days 1-4 and pemetrexed disodium IV over 10
      minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of
      disease progression or unacceptable toxicity. Patients may continue methoxyamine and
      pemetrexed disodium beyond course 6 if the patient continues to benefit from treatment at the
      discretion of the treating physician.

      After completion of study treatment, patients are followed up for 8 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (methoxyamine, pemetrexed disodium, cisplatin)ExperimentalPatients receive methoxyamine PO on days 1-4, pemetrexed disodium IV over 10 minutes on day 1, and cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond course 6 if the patient continues to benefit from treatment at the discretion of the treating physician.
  • Cisplatin
  • Methoxyamine
  • Pemetrexed Disodium
Arm B (methoxyamine, pemetrexed disodium)ExperimentalPatients receive methoxyamine PO on days 1-4 and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond course 6 if the patient continues to benefit from treatment at the discretion of the treating physician.
  • Methoxyamine
  • Pemetrexed Disodium

Eligibility Criteria

        Inclusion Criteria:

          -  Arm A dose escalation: patients with histologically or cytologically proven advanced
             solid tumors for which standard treatments are not available, or for whom the current
             dose level of cisplatin in combination with pemetrexed is appropriate; =< 2 prior
             cytotoxic chemotherapy regimen

          -  Arm A dose level 4 (75 mg/m^2 cisplatin): patients with histologically proven
             chemotherapy-naive advanced unresectable solid tumors for which pemetrexed combined
             with cisplatin is an indicated regimen (malignant mesothelioma, non-small cell lung
             cancer, ovarian cancer and thymoma)

          -  Arm A 14-patients expansion cohort: patients with histologically or cytologically
             proven chemotherapy naive unresectable malignant pleural or peritoneal mesothelioma

          -  Arm B (first stage of phase II of TRC102 and pemetrexed): patients with malignant
             pleural or peritoneal mesothelioma who had progressed while being treated with or had
             recurred within 6 months of being treated with pemetrexed and cisplatin or carboplatin
             frontline; intervening treatment is allowed

          -  Prior pemetrexed is allowed except Arm A dose level 4 (cisplatin 75 mg/m^2)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 -1 (Karnofsky >= 70%)

          -  Life expectancy of greater than 3 months

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 10.0 g/dl

          -  Prothrombin time or international normalized ratio (INR) =< 1.5 x upper limit of
             normal (ULN)

          -  Total bilirubin < 1.5 x ULN

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN or =< 5 x ULN if metastatic disease involves liver

          -  Serum creatinine =< 1.5 x ULN or a calculated creatinine clearance >= 60 ml/min/1.73
             m^2 (Cockcroft-Gault method) for patients receiving combination of cisplatin and
             pemetrexed and >= 45 ml/min/1.73 m^2 for patients receiving pemetrexed; 24 hour urine
             for creatinine clearance is acceptable if the calculated creatinine clearance is
             insufficient

          -  For patients enrolled in arm A dose level 4, arm A 14-patients expansion cohort, and
             arm B (first stage of phase II of TRC102 and pemetrexed) measurable disease is
             required according to the Response Evaluation Criteria in Solid Tumors (RECIST)
             criteria for patients with solid tumors and modified RECIST criteria as described by
             Byrne and Novak for patients with malignant pleural mesothelioma; pleural effusion and
             ascites are not considered measurable disease

          -  Patients must be able to swallow whole capsules; nasogastric or gastrointestinal
             (G)-tube administration is not allowed

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for
             the duration of study participation, and 4 months after completion of the study drugs;
             should a woman become pregnant or suspect she is pregnant while she or her partner is
             participating in this study, she should inform her treating physician immediately; men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of study participation, and 4 months after
             completion of TRC102, pemetrexed and cisplatin administration

               -  Non-childbearing potential is defined as (by other than medical reasons): >= 45
                  years of age and has not had menses for >= 2 years, amenorrheic for < 2 years
                  without hysterectomy and oophorectomy and a follicle-stimulating hormone value in
                  the postmenopausal range upon pretrial (screening) evaluation, or post
                  hysterectomy, oophorectomy or tubal ligation; documented hysterectomy or
                  oophorectomy must be confirmed with medical records of the actual procedure or
                  confirmed by ultrasound; tubal ligation must be confirmed with medical records of
                  the actual procedure otherwise the patient must be willing to use 2 adequate
                  barrier methods throughout the study, starting with the screening visit though 4
                  months after the last dose of study drugs

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events due to agents administered more than 4 weeks earlier;
             patients who have had targeted therapy will be required to wait 2 weeks due to short
             half-life of the drugs; treatment with bisphosphonates is permitted

          -  Patients who are receiving any other investigational agents

          -  Patients with active brain metastases or carcinomatous meningitis are excluded from
             this clinical trial; patients with treated brain metastases, whose brain metastatic
             disease has remained stable for greater than or equal to 4 weeks without requiring
             steroid and anti-seizure medications are eligible to participate

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to TRC102 or pemetrexed and cisplatin

          -  No studies have been performed to assess potential metabolic and transport
             interactions of TRC102; as part of the enrollment/informed consent procedures, the
             patient will be counseled on the risk of interactions with other agents, and what to
             do if new medications need to be prescribed or if the patient is considering a new
             over-the-counter medicine or herbal product; the case report form must capture the
             concurrent use of all other drugs, over-the-counter medications, or alternative
             therapies

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with TRC102

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

          -  Patients with known disorders associated with hemolysis

          -  Patients with thromboembolic disease and on anticoagulation

          -  Patients with a prior cumulative cisplatin dose > 300 mg/m^2 (pertains to Arm A only)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Arm A)
Time Frame:21 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) parameter
Time Frame:Pre-methoxyamine and cisplatin, and at 15 and 30 minutes, 1, 2, 4, 6, and 24 hours post cisplatin on course 1
Safety Issue:
Description:PK data analyses will be performed using non-compartmental methods according to the rule of linear trapezoids. Individual PK parameter estimates (e.g., maximum C concentration observed, volume in steady state, systemic clearance, half-life, and area under the curve) will be determined for methoxyamine and cisplatin for each patient and tabulated using summary statistics (means and coefficients of variation).
Measure:Establishment of pleural and peritoneal effluent-derived cell lines
Time Frame:Baseline
Safety Issue:
Description:Feasibility of establishing pleural and peritoneal effluent-derived cell lines will be reflected in the number successfully established.
Measure:Response of cultured pleural and peritoneal mesothelioma cells to cisplatin, pemetrexed, and methoxyamine
Time Frame:Baseline
Safety Issue:
Description:Results will be compared to patients' responses. Will be studied using standard experimental design approaches and generalized linear model analyses.
Measure:Objective clinical response
Time Frame:Up to 8 weeks post-treatment
Safety Issue:
Description:RECIST-defined responses will be summarized as a fraction of all subjects, and as a fraction of all subjects in the Arm A or Arm B expansion cohorts, using exact binomial 9 percent confidence intervals.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 2, 2018