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

• ClinicalTrials.gov Identifier: NCT02535312
• Recruitment Status: Active, not recruiting
• First Posted: August 28, 2015
• Last Update Posted: November 16, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Malignant Solid Neoplasm; Advanced Peritoneal Malignant Mesothelioma; Advanced Pleural Malignant Mesothelioma; Recurrent Peritoneal Malignant Mesothelioma; Recurrent Pleural Malignant Mesothelioma; Refractory Malignant Solid Neoplasm; Unresectable Solid Neoplasm	Drug: Cisplatin; Drug: Methoxyamine; Drug: Pemetrexed Disodium	Phase 1; Phase 2

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 58 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 11, 2015
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (methoxyamine, pemetrexed disodium, cisplatin); 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.	Drug: Cisplatin; Given IV; Other Names: Abiplatin; 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; Platosin; Drug: Methoxyamine; Given PO; Other Name: TRC102 Base; Drug: Pemetrexed Disodium; Given IV; Other Names: Alimta; Almita; 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 Salt
Experimental: Arm B (methoxyamine, pemetrexed disodium); 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.	Drug: Methoxyamine; Given PO; Other Name: TRC102 Base; Drug: Pemetrexed Disodium; Given IV; Other Names: Alimta; Almita; 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 Salt

Outcome Measures

Primary Outcome Measures :

1. Dose-limiting toxicity (Arm A) [ Time Frame: 21 days ]
   Dose-limiting toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 as of April 1, 2018).
2. Response rate (Arm B) [ Time Frame: Up to 8 weeks post-treatment ]
   Will be measured using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

Secondary Outcome Measures :

1. 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 ]
   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).
2. Establishment of pleural and peritoneal effluent-derived cell lines [ Time Frame: Baseline ]
   Feasibility of establishing pleural and peritoneal effluent-derived cell lines will be reflected in the number successfully established.
3. Response of cultured pleural and peritoneal mesothelioma cells to cisplatin, pemetrexed, and methoxyamine [ Time Frame: Baseline ]
   Results will be compared to patients' responses. Will be studied using standard experimental design approaches and generalized linear model analyses.
4. Objective clinical response [ Time Frame: Up to 8 weeks post-treatment ]
   RECIST-defined responses will be summarized as a fraction of all subjects, and as a fraction of all subjects in Arm B, using exact binomial 9 percent confidence intervals.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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
• 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 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
• The effects of TRC102 on the developing human fetus are unknown; for this reason and because TRC102 as well as other therapeutic agents used in this trial are known to be teratogenic, 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 because TRC102 is agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TRC102, breastfeeding should be discontinued if the mother is treated with TRC102; these potential risks may also apply to other agents used in this study
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with TRC102; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• 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)

Contacts and Locations

Locations

United States, California

City of Hope Comprehensive Cancer Center

Duarte, California, United States, 91010

Los Angeles County-USC Medical Center

Los Angeles, California, United States, 90033

USC / Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

Keck Medical Center of USC Pasadena

Pasadena, California, United States, 91105

University of California Davis Comprehensive Cancer Center

Sacramento, California, United States, 95817

United States, Colorado

University of Colorado Hospital

Aurora, Colorado, United States, 80045

United States, Maryland

University of Maryland/Greenebaum Cancer Center

Baltimore, Maryland, United States, 21201

United States, Michigan

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

Mayo Clinic in Rochester

Rochester, Minnesota, United States, 55905

United States, Ohio

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Pennsylvania

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States, 15232

United States, Tennessee

Vanderbilt Breast Center at One Hundred Oaks

Nashville, Tennessee, United States, 37204

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States, 37232

United States, Wisconsin

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Marianna Koczywas; City of Hope Comprehensive Cancer Center LAO

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02535312
• Other Study ID Numbers: NCI-2015-00127; NCI-2015-00127 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); PHI-76; 9837 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO ); 9837 ( Other Identifier: CTEP ); UM1CA186689 ( U.S. NIH Grant/Contract ); UM1CA186705 ( U.S. NIH Grant/Contract ); UM1CA186717 ( U.S. NIH Grant/Contract ); ZIABC011078 ( U.S. NIH Grant/Contract )
• First Posted: August 28, 2015
• Last Update Posted: November 16, 2022
• Last Verified: July 2022

Additional relevant MeSH terms:

Neoplasms; Mesothelioma; Mesothelioma, Malignant; Lung Neoplasms; Recurrence; Disease Attributes; Pathologic Processes; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Cisplatin; Pemetrexed; Antineoplastic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors