Symptoms and General Pathology

All Conditions

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Recurrence

Mesothelioma

Mesothelioma, Malignant

Lung Neoplasms

Disease Attributes

Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Mesothelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Pleural Neoplasms

Lung Diseases

Respiratory Tract Diseases

Malignant Mesothelioma

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Amino Acids

Vitamins

Carboplatin

Pemetrexed

Cisplatin

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Glutamic Acid

Folinic Acid

Folate

Vitamin B9

Patients receive methoxyamine PO QD on days 1-4, pemetrexed disodium 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.

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.

Methoxyamine

Pemetrexed Disodium

Marianna Koczywas

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.

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

Phase I Study of TRC102 in Combination With Cisplatin and Pemetrexed in Patients With Advanced Solid Tumors / Phase II Study of TRC102 With Pemetrexed in Patients Refractory to Pemetrexed and Cisplatin or Carboplatin

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.

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.

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

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).

Overall survival will be summarized as time from first protocol treatment until death from any cause, using the product-limit Kaplan-Meier estimator.

National Cancer Institute (NCI)

"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.

TRC102 50 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 1 - 50mg TRC102, 60mg/m^2 Cisplatin (Phase I)

TRC102 75 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 2 - 75mg TRC102, 60mg/m^2 Cisplatin (Phase I)

TRC102 100 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 3 - 100mg TRC102, 60mg/m^2 Cisplatin (Phase I)

TRC102 100 mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 75 mg/m\^2 IV over 30-60 min day1

Arm A, Dose Level 4 - 100mg TRC102, 75mg/m^2 Cisplatin (Phase I)

TRC102 50mg PO on days 1-4; Pemetrex 500mg/m\^2 IV over 10 min day 1

Arm B, Dose Level 1 - 50mg TRC102 (Phase II)

TRC102 50 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 75 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 100 mg/dayPO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 100 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 75 mg/m\^2 IV over 30-60 min day1

TRC102 50mg/day PO on days 1-4; Pemetrex 500mg/m\^2 IV over 10 min day 1

Total

Age, Continuous

Sex: Female, Male

Caucasian

Hispanic

Unknown

Asian

Race/Ethnicity, Customized

United States

Region of Enrollment

0=Asymptomatic and fully active

1=Symptomatic; fully ambulatory; restricted in physically strenuous activity

ECOG performance status

Paul Frankel, Ph.D.

TRC102 100/day mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 100/day mg PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 75 mg/m\^2 IV over 30-60 min day1

Number of Participants With at Least One Dose Limiting Toxicity (DLT) - Phase I

Patients receive starting dose of TRC102 50 mg/day PO on days 1-4, 500 mg/m\^2 pemetrexed disodium IV over 10 minutes, and 60 or 75 mg/m\^2 of 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 TRC102 and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Cisplatin: Given IV

TRC102: Given PO

Pemetrexed Disodium: Given IV

Treatment (TRC102, Pemetrexed Disodium, Cisplatin)

Maximum Tolerated Dose (MTD)

TRC102 100 mg/day PO days 1-4; Pemetrex 500 mg/m\^2 IV over 10 min day1; Cisplatin 60 mg/m\^2 IV over 30-60 min day1

TRC102 50 mg/day PO on days 1-4; Pemetrex 500mg/m\^2 IV over 10 min day 1

Number of Subject With Overall Response

Patients receive 50, 75 or 100 mg/day of TRC102 PO QD on days 1-4, 500 mg/m\^2 of pemetrexed disodium IV over 10 minutes, and 60 or 75 mg/m\^2 of 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 TRC102 and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Arm A (TRC102, Pemetrexed Disodium, Cisplatin) - Phase I

Patients receive 50 mg/day of TRC102 PO QD on days 1-4 and 500 mg/m\^2 of 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 TRC102 and pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the discretion of the treating physician.

Arm B (TRC102, Pemetrexed Disodium) - Phase II

Pre-specified in the Study Protocol to collect, analyze, and report data for this Outcome Measure by Phase and not by dose-level.

Spots Global Cancer Trial Database for advanced peritoneal malignant mesothelioma