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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 Cisplatin and Pemetrexed

Published: January 28, 2016

Primary Outcome Measures

  • 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 ] [ Designated as safety issue: Yes ]
  • Response rate using RECIST (Arm B) [ Time Frame: Up to 8 weeks post-treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures

  • Establishment of pleural and peritoneal effluent-derived cell lines [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Feasibility of establishing pleural and peritoneal effluent-derived cell lines will be reflected in the number successfully established.
  • Objective clinical response [ Time Frame: Up to 8 weeks post-treatment ] [ Designated as safety issue: No ]
    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.
  • Pharmacokinetic (PK) parameter [ Time Frame: Pre-methoxyamine and cisplatin, and at 30 minutes, 1, 2, 4, 6, 24, and 167 hours post cisplatin on course 1 ] [ Designated as safety issue: No ]
    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).
  • Response of cultured pleural and peritoneal mesothelioma cells to cisplatin, pemetrexed, and methoxyamine [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Results will be compared to patients’ responses. Will be studied using standard experimental design approaches and generalized linear model analyses.


Inclusion Criteria
  • Arm A dose escalation: patients with histologically or cytologically proven advanced solid tumors for which standard treatments are not available; =< 2 prior cytotoxic chemotherapy regimen; prior cumulative dose of cisplatin < 300 mg/m^2
  • Arm A dose level 4 (75 mg/m^2 cisplatin): patients with histologically proven chemotherapy-naïve 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 naïve 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 3 months of being treated with pemetrexed and cisplatin or carboplatin frontline
  • 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 [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 and for the duration of study participation; 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
  • 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


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