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.
|First Received Date||August 27, 2015|
|Last Changed Date||April 23, 2018|
|Start Date||August 11, 2015|
|Anticipated Primary Completion Date||December 31, 2018|
|Primary Outcome Measures||
Dose-limiting toxicity, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 as of April 1, 2018) (Arm A) [Time Frame: 21 days]
Response rate using Response Evaluation Criteria in Solid Tumors (RECIST) (Arm B) [Time Frame: Up to 8 weeks post-treatment]
|Secondary Outcome Measures||
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]
Establishment of pleural and peritoneal effluent-derived cell lines [Time Frame: Baseline]
Response of cultured pleural and peritoneal mesothelioma cells to cisplatin, pemetrexed, and methoxyamine [Time Frame: Baseline]
Objective clinical response [Time Frame: Up to 8 weeks post-treatment]
|Phase||Phase 1/Phase 2|
|Study Arms / Comparison Groups||2 / 0|
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)
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.
|Ages||18 Years - N/A|
|Accepts Healthy Volunteers||No|
- 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
- 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)
|Sponsor||National Cancer Institute (NCI)|
|Verification Date||April 2018|