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.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) for the combination of methoxyamine (TRC102) 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 describe responses to the drug combination at each dose level. (Arm A) IV. 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) once daily (QD) 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 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician. ARM B: Patients receive methoxyamine PO QD on days 1-4 and pemetrexed disodium IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond cycle 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
30
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Keck Medical Center of USC Pasadena
Pasadena, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Mayo Clinic in Rochester
Rochester, Minnesota, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States
...and 4 more locations
Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I
Dose-limiting toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Pre-specified DLT criteria included the following adverse events (AE), judged to be at least possibly related to study therapy: grade 3 or greater non-hematologic toxicity, grade 3 thrombocytopenia with bleeding, any grade 4 thrombocytopenia, grade 4 febrile neutropenia lasting \> 7 day, any grade febrile neutropenia, any grade 5 toxicity. Treatment delay of cycle 2 by more than 2 weeks and inability to administer 3 of the 4 doses due to toxicity in the first treatment course were also considered DLTs. Controllable nausea, vomiting and diarrhea, electrolyte toxicities correctable (to baseline or grade 1) with repletion and grade 3 creatinine elevation correctable (to grade 1 or less) with IV hydration were not considered DLT's.
Time frame: During the first cycle of treatment, up to 21 days
Maximum Tolerated Dose (MTD)
The maximum tolerated dose of TRC102 in combination with 500mg/m\^2 IV of Pemetrex and 60 or 75 mg/m\^2 IV of Cisplatin is based on toxicities observed during the first cycle and is defined as the highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. Dose escalations proceeded according to a standard 3+3 design.
Time frame: 21 days from start of treatment, up to 2 years
Number of Subject With Overall Response
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR
Time frame: Up to 8 weeks post-treatment
Progression-free Survival
Progression-free survival will be summarized as time from first protocol treatment until progression or death from any cause, using the product-limit Kaplan-Meier estimator. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECISTv1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: From start of treatment to time of progression or death from any cause, whichever occurs first, assessed up to at least 1 year
Overall Survival
Overall survival will be summarized as time from first protocol treatment until death from any cause, using the product-limit Kaplan-Meier estimator.
Time frame: From start of treatment to time of death from any cause, assessed up to at least 3 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.