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

Advanced Malignant Solid Neoplasm Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02535312
• Other study ID #: NCI-2015-00127
• Secondary ID: NCI-2015-00127PH
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 8, 2016
• Est. completion date: October 17, 2024

Study information

• Verified date: April 2024
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 30
• Est. completion date: October 17, 2024
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Advanced Malignant Solid Neoplasm
• Advanced Peritoneal Malignant Mesothelioma
• Advanced Pleural Malignant Mesothelioma
• Lung Neoplasms
• Mesothelioma
• Mesothelioma, Malignant
• Neoplasms
• Recurrence
• Recurrent Peritoneal Malignant Mesothelioma
• Recurrent Pleural Malignant Mesothelioma
• Refractory Malignant Solid Neoplasm
• Unresectable Solid Neoplasm

Intervention

Drug:
• Cisplatin
Given IV
• Methoxyamine
Given PO
• Pemetrexed Disodium
Given IV

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	UCHealth University of Colorado Hospital	Aurora	Colorado
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	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	University of Wisconsin Carbone Cancer Center - University Hospital	Madison	Wisconsin
United States	Vanderbilt Breast Center at One Hundred Oaks	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Keck Medical Center of USC Pasadena	Pasadena	California
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	During the first cycle of treatment, up to 21 days
Primary	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.	21 days from start of treatment, up to 2 years
Primary	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	Up to 8 weeks post-treatment
Secondary	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).	From start of treatment to time of progression or death from any cause, whichever occurs first, assessed up to at least 1 year
Secondary	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.	From start of treatment to time of death from any cause, assessed up to at least 3 years