TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

Phase 1

Completed

Conditions: Metastatic Colon Carcinoma
Solid Tumors
Granulosa Cell Ovarian Cancer
Lymphomas
NSCLC

Interventions: Drug: TRC102
Diagnostic Test: CT scan
Other: Lomotil
Other: Prochlorperazine
Other: Metoclopramide
Other: 5-HT3 antagonist
Other: Aprepitant
Procedure: Biopsy

Registration Number: NCT01851369

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

- Methoxyamine hydrochloride (TRC102) is a new cancer treatment drug that may help improve the results of chemotherapy. It blocks tumor cells' attempts to repair damaged deoxyribonucleic acid (DNA), which may allow chemotherapy to kill the cells more easily. Researchers want to see how well it works with temozolomide, a chemotherapy drug that is designed to damage tumor cell DNA. These drugs will be given to people who have advanced solid tumors or lymphomas that have not responded to earlier treatments.

Objectives:

- To test the safety and effectiveness of TRC102 and temozolomide for advanced solid tumors and lymphomas.

Eligibility:

- Individuals at least 18 years of age who have advanced solid tumors or lymphomas that have not responded to earlier treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor samples may also be collected. The size and location of the tumors will be determined with imaging studies.

* Participants will take TRC102 and temozolomide for 28-day cycles of treatment. They will take temozolomide and TRC 102 by mouth once a day on days 1-5. Participants will keep a diary to record doses and any side effects.

* Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples will also be collected.

* Participants will continue their treatment as long as the cancer does not grow and there are no severe side effects.

Detailed Description: Background:

* Base excision repair (BER) of deoxyribonucleic acid (DNA) repair pathway has been implicated in resistance to both alkylating and antimetabolite chemotherapy.

* TRC102 (methoxyamine hydrochloride (HCl) acts through a novel mechanism to inhibit BER and has demonstrated the ability to potentiate the activity of the alkylating agent temozolomide (TMZ), in vitro and in vivo. We hypothesize that TRC102 can be safely co-administered with TMZ and would potentiate DNA damage caused by TMZ, resulting in antitumor responses.

* Based on responses measured during the Phase I portion of the trial, we will further explore the efficacy of this combination in patients with metastatic colon carcinoma, non-small cell lung cancer (NSCLC), and granulosa cell ovarian cancer

Primary Objective:

* To establish the safety, tolerability, and maximum tolerated dose (MTD) of oral TRC102 in combination with oral TMZ in patients with refractory solid tumors

* Evaluate the pharmacokinetic (PK) profile of oral TRC102 when administered in combination with TMZ.

* To explore the response rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer

Secondary Objective:

-To explore the progression free survival rate of this combination in patients with colon cancer, NSCLC, and granulosa cell ovarian cancer

Exploratory Objectives:

* Investigate tumor genomic and transcriptomic alterations potentially associated with sensitivity and/or the development of resistance to TRC102 and temozolomide.

* Determine the effects of the study treatment on the level of histone gamma-H2A histone family member X (H2AX) in circulating tumor cells (CTCs) and tumor and correlate the gamma-H2AX response in tumor and CTCs

* Determine the effects of the study treatment on the levels of cleaved caspase 3, epithelial- mesenchymal transition, and abdominoperineal excision (APE) in tumor and CTCs

* Determine and characterize the effects of study treatment on erythrocytes

* Characterize the clinical presentation of hemolysis observed in earlier study subjects and explore the possible mechanisms

Eligibility:

* Phase I: histologically confirmed solid tumors that have progressed on standard therapy known to prolong survival or for which no standard treatment options exist

* Phase II: histologically confirmed adenocarcinoma of the colon post at least two lines of therapy, NSCLC post at least two lines of therapy, or granulosa cell ovarian cancer post at least one line of therapy

* No major surgery, radiation, or chemotherapy within 4 weeks prior to entering the study

* Adequate organ function

* Healthy adult volunteers greater than or equal to 18 years of age will be consented to donate research blood

Please note: healthy adult volunteers will no longer be recruited to provide blood for this study as we will no longer perform the hemolysis analysis.

Study Design: Phase I

* This is an open-label Phase I trial; traditional 3+3 design.

* Oral TRC102 and oral TMZ will be administered daily, days 1-5 in 28-day cycles

* Once the MTD is established, up to 15 additional patients will be enrolled at the MTD to further evaluate that dose for PK and pharmacodynamic (PD) endpoints for evidence of DNA damage and apoptosis.

* During the escalation phase, tumor biopsies will be optional. During the expansion phase, (once MTD is reached), mandatory paired tumor biopsies will be pursued in the 15 additional patients enrolled to further evaluate progressive disease (PD) endpoints.

Phase II

* This is a 3-arm Simon 2-stage design trial evaluating independently the response rate of patients with colon, NSCLC, and granulosa cell ovarian cancer.

* Patients with a body surface area (BSA) of greater than or equal to 1.6 m(2) will receive 125 mg of TRC 102 and 150 mg/m(2) of TMZ PO qday x 5 every 28 days (DL6). Patients with a BSA of \<1.6 m(2) will receive 100 mg of TRC 102 and 150 mg/m(2) of TMZ by mouth (PO) every (q)day x 5 every 28 days (Dose Level (DL)5). Each cycle will be 28 days.

* The accrual ceiling for the Phase II portion is 75 patients.

* Mandatory paired tumor biopsies will be pursued to further evaluate PD endpoints.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 93

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	Prochlorperazine	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	CT scan	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	5-HT3 antagonist	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	Biopsy	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	Lomotil	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	Aprepitant	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	Metoclopramide	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.
Combination Treatment with Oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ)	TRC102	Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.

Primary Outcome Measures

Name	Time	Method
The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ	At dose-limiting toxicity (DLT) determined in the first cycle; approximately 28 days	Dose-limiting toxicities (DLTs) are defined as toxicities occurring within the first cycle of treatment felt to be possibly, probably, or definitely related to administration of study drugs and fulfilling one of the following criteria: Grade 4 neutropenia, febrile neutropenia, neutropenic infection: Grade ≥ 3 neutropenia with grade ≥ 3 infection, Grade ≥ 3 thrombocytopenia, a drop in hemoglobin (Hgb) ≥3.0 g/dL over one week, and all Grade ≥ 3 non-hematologic toxicity other than: non-bloody diarrhea Grade 3 that is corrected to Grade ≤ 2 within 24 hours, nausea and vomiting Grade 3 that is corrected to Grade ≤ 1 within 24 hours, creatinine Grade 3 corrected to Grade ≤ 1 within 48 hours, and Grade 3 electrolyte abnormalities. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening. And Grade 5 is death related to adverse event.
Phase 1 Pharmacokinetic (PK) Profile: the Percentage of TRC102 Dose Recovered From Participant Urine in Participants Treated With Oral TRC102 in Combination With Temozolomide (TMZ)	First day of treatment	Urine samples will be collected, and pharmacokinetics will be assessed in phase I portion of the study. Samples will be analyzed using a validated liquid chromatography-mass spectrometry (LC-MS) or liquid chromatography with tandem mass spectrometry (LC-MS-MS) method.
Phase 1 Maximum Tolerated Dose (MTD) of Oral Temozolomide (TMZ) in Participants With Refractory Solid Tumors.	First cycle of treatment; approximately 28 days	The MTD or recommended Phase II dose is the dose level at which no more than 1 of 6 participants experience dose-limiting toxicity (DLT) during the first cycle of treatment, and the dose below that at which at least 2 (of ≤ 6) participants have DLT as a result of the drug. DLTs will be defined as toxicities occurring within the first cycle of treatment and is felt to be possibly, probably, or definitely related to administration of study drugs and fulfills one of the following criteria: hematologic toxicities - Grade 4 neutropenia, febrile neutropenia, neutropenic infection: Grade ≥ 3 neutropenia with grade ≥ 3 infection, Grade ≥ 3 thrombocytopenia, a drop in hemoglobin (Hgb) ≥3.0 g/dL over one week, any degree of lymphopenia, or leukopenia in the absence of grade 4 neutropenia will not be considered dose limiting, and Grade ≥ 3 non-hematologic toxicity. Grade ≥ 3 electrolyte abnormalities will not be considered dose limiting.
Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer	Response rate at one year	Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Complete response (CR) is disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on-study (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.
Phase 1 Pharmacokinetic (PK) Profile of Oral TRC102 When Administered in Combination With Temozolomide (TMZ) as Measured by Maximum Plasma Concentration (Cmax) of TRC102: Mean (Standard Deviation)	First 5 days of treatment	Blood samples will be collected, and pharmacokinetics will be assessed in the phase I portion of the study. Samples will be analyzed using a validated LC-MS or LC-MS/MS method in human plasma. The maximum observed analyte concentration in plasma was reported.
Phase 1 Maximum Tolerated Dose (MTD) of Oral TRC102 in Participants With Refractory Solid Tumors.	First cycle of treatment; approximately 28 days	The MTD or recommended Phase II dose is the dose level at which no more than 1 of 6 participants experience dose-limiting toxicity (DLT) during the first cycle of treatment, and the dose below that at which at least 2 (of ≤ 6) participants have DLT as a result of the drug. DLTs are defined as toxicities occurring within the first cycle of treatment felt to be possibly, probably, or definitely related to administration of study drugs and fulfilling one of the following criteria: Grade 4 neutropenia, febrile neutropenia, neutropenic infection: Grade ≥ 3 neutropenia with grade ≥ 3 infection, Grade ≥ 3 thrombocytopenia, a drop in hemoglobin (Hgb) ≥3.0 g/dL over one week, and all Grade ≥ 3 non-hematologic toxicities other than: non-bloody diarrhea Grade 3 that is corrected to Grade ≤ 2 within 24 hours, nausea and vomiting Grade 3 that is corrected to Grade ≤ 1 within 24 hours, creatinine Grade 3 corrected to Grade ≤ 1 within 48 hours, and Grade 3 electrolyte abnormalities.

Secondary Outcome Measures

Name	Time	Method
Phase 2: Progression Free Survival Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer	Duration on study, an average of 130 days	Progression free survival rate of this combination in participants with colon cancer, NSCLC, and granulosa cell ovarian cancer. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum onstudy (this includes the baseline sum if that is the smallest on study). The appearance of one or more new lesions is also considered progressions.