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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 Pemetrexed Disodium and Cisplatin or Carboplatin

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02535312
First received: August 27, 2015
Last updated: June 26, 2017
Last verified: May 2017
  Purpose
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.

Condition Intervention Phase
Advanced Malignant Solid Neoplasm Advanced Peritoneal Malignant Mesothelioma Advanced Pleural Malignant Mesothelioma Recurrent Malignant Solid Neoplasm Recurrent Peritoneal Malignant Mesothelioma Recurrent Pleural Malignant Mesothelioma Stage III Non-Small Cell Lung Cancer Stage III Ovarian Cancer Stage III Pleural Mesothelioma Stage IIIA Non-Small Cell Lung Cancer Stage IIIA Ovarian Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IIIB Ovarian Cancer Stage IIIC Ovarian Cancer Stage IV Non-Small Cell Lung Cancer Stage IV Ovarian Cancer Stage IV Pleural Mesothelioma Thymoma Unresectable Solid Neoplasm Drug: Cisplatin Other: Laboratory Biomarker Analysis Drug: Methoxyamine Drug: Pemetrexed Disodium Other: Pharmacological Study Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase I Study of TRC102 in Combination With Cisplatin and Pemetrexed in Patients With Advanced Solid Tumors, With Expansion Cohort in Mesothelioma / Phase II Study of TRC102 With Pemetrexed in Patients Refractory to Pemetrexed and Cisplatin or Carboplatin

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

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 ]
  • Response rate using RECIST (Arm B) [ Time Frame: Up to 8 weeks post-treatment ]

Secondary Outcome Measures:
  • 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.

  • 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 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 15 and 30 minutes, 1, 2, 4, 6, and 24 hours post cisplatin on course 1 ]
    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 ]
    Results will be compared to patients' responses. Will be studied using standard experimental design approaches and generalized linear model analyses.


Estimated Enrollment: 58
Actual Study Start Date: August 11, 2015
Estimated Primary Completion Date: August 31, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (methoxyamine, pemetrexed disodium, cisplatin)
Patients receive methoxyamine PO on days 1-4, pemetrexed disodium IV over 10 minutes on day 1, and cisplatin IV over 30-60 minutes on day 1. Treatment repeats every 21 days for 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.
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
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Methoxyamine
Given PO
Other Name: TRC102
Drug: Pemetrexed Disodium
Given IV
Other Names:
  • Alimta
  • 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
Other: Pharmacological Study
Correlative studies
Experimental: Arm B (methoxyamine, pemetrexed disodium)
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.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Methoxyamine
Given PO
Other Name: TRC102
Drug: Pemetrexed Disodium
Given IV
Other Names:
  • Alimta
  • 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
Other: Pharmacological Study
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

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)

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) 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
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 (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
  • 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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02535312

Locations
United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Marianna Koczywas    800-826-4673    becomingapatient@coh.org   
Principal Investigator: Marianna Koczywas         
Los Angeles County-USC Medical Center Recruiting
Los Angeles, California, United States, 90033
Contact: Anthony El-Khoueiry    323-865-0451      
Principal Investigator: Anthony El-Khoueiry         
USC / Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Anthony El-Khoueiry    323-865-0451      
Principal Investigator: Anthony El-Khoueiry         
Keck Medical Center of USC Pasadena Recruiting
Pasadena, California, United States, 91105
Contact: Anthony El-Khoueiry    323-865-0451      
Principal Investigator: Anthony El-Khoueiry         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Karen L. Kelly    916-734-3089      
Principal Investigator: Karen L. Kelly         
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion Recruiting
Aurora, Colorado, United States, 80045
Contact: Stephen Leong    720-848-0650      
Principal Investigator: Stephen Leong         
United States, Maryland
University of Maryland/Greenebaum Cancer Center Recruiting
Baltimore, Maryland, United States, 21201
Contact: Edward A. Sausville    800-888-8823      
Principal Investigator: Edward A. Sausville         
United States, Michigan
University of Michigan Comprehensive Cancer Center Suspended
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Mayo Clinic Suspended
Rochester, Minnesota, United States, 55905
United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Gregory A. Otterson    800-293-5066    Jamesline@osumc.edu   
Principal Investigator: Gregory A. Otterson         
United States, Pennsylvania
University of Pittsburgh Cancer Institute (UPCI) Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Liza C. Villaruz    412-647-8073      
Principal Investigator: Liza C. Villaruz         
United States, Tennessee
Vanderbilt University/Ingram Cancer Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Leora Horn    800-811-8480      
Principal Investigator: Leora Horn         
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: Ticiana B. Leal    877-405-6866      
Principal Investigator: Ticiana B. Leal         
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     History of Changes
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 )
P30CA033572 ( US NIH Grant/Contract Award Number )
UM1CA186689 ( US NIH Grant/Contract Award Number )
UM1CA186705 ( US NIH Grant/Contract Award Number )
UM1CA186717 ( US NIH Grant/Contract Award Number )
ZIABC011078 ( US NIH Grant/Contract Award Number )
Study First Received: August 27, 2015
Last Updated: June 26, 2017

Additional relevant MeSH terms:
Lung Neoplasms
Neoplasms
Carcinoma, Non-Small-Cell Lung
Ovarian Neoplasms
Mesothelioma
Thymoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Mesothelial
Neoplasms, Complex and Mixed
Thymus Neoplasms
Lymphatic Diseases
Cisplatin
Pemetrexed

ClinicalTrials.gov processed this record on June 27, 2017