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Combination treatment with oral methoxyamine hydrochloride (TRC102) and oral Temozolomide (TMZ) for days 1-5 of 28-day cycles.

Methoxyamine hydrochloride (TRC102) has been shown to potentiate the activity of temozolomide by preventing base excision repair (BER) and allowing cleavage of TRC102 bound deoxyribonucleic acid (DNA), which will cause DNA strand breaks in cancer cells. We hypothesize that oral TRC102 can be safely co-administered with Temozolomide (TMZ) and would potentiate DNA damage caused by TMZ resulting in antitumor responses.

TRC102

CT scans will be performed at baseline, and repeat scans will be performed every 2 cycles (every 3 cycles for participants on study more than one year).

CT scan

If diarrhea develops and does not have an identifiable cause other than study drug administration, anti-diarrheal's such as Lomotil (diphenoxylate hydrochloride (HCl) 2.5 mg + atropine sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg by mouth (po) after the first unformed stool with 2 mg po every 2 hours as long as unformed stools continue (4 mg every 4 hours while asleep). No more than 16 mg of loperamide should be taken in during a 24-hour period.

Lomotil

If a participant develops nausea/vomiting, an anti-emetic such as prochlorperazine may be given.

If a participant develops nausea/vomiting, an anti-emetic such as metoclopramide may be given.

If a participant develops nausea/vomiting, an anti-emetic such as 5-HT3 antagonist may be given.

5-HT3 antagonist

If a participant develops nausea/vomiting, an anti-emetic such as aprepitant may be given.

Tumor biopsies will be optional during the escalation phase.

Biopsy

Alice P Chen, M.D.

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.

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.

TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

A Phase I/II Trial of TRC102 (Methoxyamine HCl) in Combination With Temozolomide in Patients With Relapsed Solid Tumors and Lymphomas

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

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.

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

Principal Investigator

92/93 participants were analyzed because one participant in phase 1 dose level 3 declined to participate (before treatment started).

Cycle = 28 days; Methoxyamine (TRC102) 125mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 75mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 1 Methoxyamine (TRC102) 125mg & Temozolomide 75mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 50mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 125mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 2 Methoxyamine (TRC102) 50mg & Temozolomide 125mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 50mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 3 Methoxyamine (TRC102) 50mg & Temozolomide 150mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 75mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 100mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 125mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 150mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 150mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 200mg/m\^2 PO QD on days 1-5.

Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2

Cycle = 28 days; Methoxyamine (TRC102) 125mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5 for participants with a body surface area (BSA) ≥ 1.6 m\^2 OR Cycle = 28 days; Methoxyamine (TRC102) 100mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 150mg/m\^2 PO QD on days 1-5 for participants with a body surface area (BSA) \< 1.6 m\^2.

Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area)

Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area)

Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area)

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Baseline data was collected and is reported here for all 93/93 participants, including one participant on phase 1 dose level 4 who declined to participate (before treatment started).

Dr. Alice P.Chen

Complete Response

Partial Response

Stable Disease

Progressive Disease

Not Assessed Due to Death on Study

Not Assessed Due to Clinical Progression

Not Assessed Due to Refusing Further Treatment

A total of 41/93 participants were analyzed: 0/52 phase 1 participants were analyzed as this outcome measure was for the phase 2 participants only; 41/41 phase 2 participants were evaluable for response rate.

Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer

A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week

Grade 4 Neutropenia

Grade 4 Thrombocytopenia

36/37 participants in the phase I dose escalation cohort were analyzed because one participant in dose level 3 declined to participate (before treatment started).

The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ

51/52 participants were analyzed for plasma PK in phase 1 because one participant declined to participate (before treatment started).

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)

51/52 participants were analyzed for urine PK in phase 1 because one participant declined to participate (before treatment started).

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)

All participants on phase I who received at least one dose of TRC102 and Temozolomide.

All Participants

51/52 participants were analyzed in phase 1 because one participant declined to participate (before treatment started).

Phase 1 Maximum Tolerated Dose (MTD) of Oral TRC102 in Participants With Refractory Solid Tumors.

Phase 1 Maximum Tolerated Dose (MTD) of Oral Temozolomide (TMZ) in Participants With Refractory Solid Tumors.

41/41 participants in phase 2 were analyzed. 0/52 participants in phase 1 were analyzed as this was a Phase 2-specific outcome measure, thus the table reports data for phase 2 reporting groups only.

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

Phase 1 and Phase 2: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

No participants were enrolled in this group. Cycle = 28 days; Methoxyamine (TRC102) 25mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 75mg/m\^2 PO QD on days 1-5.

Phase (Ph) 1 Dose Level -2 Methoxyamine (TRC102) 25mg & Temozolomide (TMZ) 75mg/m^2

No participants were enrolled in this group. Cycle = 28 days; Methoxyamine (TRC102) 25mg by mouth (PO) everyday (QD) on days 1-5; Temozolomide (TMZ) 100mg/m\^2 PO QD on days 1-5.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas	NCT01851369	Lymphomas Solid Tumors NSCLC Metastatic Colo... Granulosa Cell ...	TRC102 CT scan Lomotil Prochlorperazin... Metoclopramide 5-HT3 antagonis... Aprepitant Biopsy	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas	NCT01851369	Lymphomas Solid Tumors NSCLC Metastatic Colo... Granulosa Cell ...	TRC102 CT scan Lomotil Prochlorperazin... Metoclopramide 5-HT3 antagonis... Aprepitant Biopsy	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for granulosa cell ovarian cancer