Lymphomas, Solid Tumors, NSCLC, Metastatic Colon Carcinoma, Granulosa Cell Ovarian Cancer
Conditions
Keywords
Solid Tumors, Lymphomas, DNA Damage, Pharmacodynamics, Pharmacokinetics
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.
Interventions
DRUGTRC102
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.
DIAGNOSTIC_TESTCT scan
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).
OTHERLomotil
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.
OTHERProchlorperazine
If a participant develops nausea/vomiting, an anti-emetic such as prochlorperazine may be given.
OTHERMetoclopramide
If a participant develops nausea/vomiting, an anti-emetic such as metoclopramide may be given.
OTHER5-HT3 antagonist
If a participant develops nausea/vomiting, an anti-emetic such as 5-HT3 antagonist may be given.
OTHERAprepitant
If a participant develops nausea/vomiting, an anti-emetic such as aprepitant may be given.
PROCEDUREBiopsy
Tumor biopsies will be optional during the escalation phase.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Eligibility Criteria (Patients) * 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 colorectal adenocarcinoma post at least two lines of therapy, non-small cell lung cancer (NSCLC) post at least two lines of therapy, or granulosa cell ovarian cancer post at least one line of therapy. Patients must have measurable disease. * Age greater than18 years. Because no dosing or adverse event data are currently available on the use of methoxyamine hydrochloride (TRC102) in combination with Temozolomide (TMZ) in patients less than 18 years of age, children are excluded from this study. * Patients enrolling in the expansion cohorts must have disease amenable to biopsy and be willing to undergo pre-and post-treatment biopsies. * Eastern Cooperative Oncology Group (ECOG) performance status less than 2 (Phase I), less than or equal to 1(Phase II). * Life expectancy of greater than 3 months * Patients must have normal organ and marrow function as defined below: * Absolute neutrophil count greater than 1,500/mcL * Hemoglobin greater than or equal to 10 g/dL without transfusion within 1 week prior to enrollment Platelets greater than or equal to 100,000/mcL Total bilirubin less than or equal to1.5 X institutional ULN Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT)(SGPT) less than or equal to 3 X institutional upper limit of normal; 5.0 x upper limit of normal (ULN) in cases of liver metastases creatinine less than or equal to 1.5 X institutional ULN OR creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels greater than 1.5 mg/dL -The effects of study drug on the developing human fetus are unknown. For this reason, 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 and for the duration of study participation and for at least 3 months after dosing with study drugs ceases. 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 3 months after completion of study drug administration. * Patients must have completed any chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks (or 5 half-lives, whichever is shorter) prior to entering the study (6 weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a Phase 0 or equivalent study and greater than or equal to 1 week from palliative radiation therapy. Patients must have recovered to eligibility levels from prior toxicity or adverse events. Treatment with bisphosphonates is permitted. * Patients must be able to swallow whole tablets or capsules; nasogastric or gastric (G)-tube administration is not allowed. * Ability to understand and the willingness to sign a written informed consent document and to undergo tumor biopsies in the expansion phase.
Exclusion criteria
(Patients) * Patients who are actively 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. * Phase II only: No other prior malignancies are allowed except for the following: * Adequately managed stage 0 (carcinoma in situ), I, or II basal cell or squamous cell carcinoma from which the patient is currently in complete remission. * Any other cancer from which the patient has been disease-free for three years. * Adequately managed stage I or II well differentiated thyroid or prostate cancer is also eligible, wherein the patient is not required to be in complete remission. * Phase II only: patients with colorectal cancer with known MSI-high disease who have not previously been treated with immunotherapy or who have refused treatment with immunotherapy. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to TRC102 or TMZ. * Uncontrolled intercurrent illness including, but not limited to, serious untreated 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 the effects of the study drugs on the developing fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug. * HIV-positive patients on combination antiretroviral therapy are ineligible because of possible pharmacokinetic (PK) interactions with TRC102. (Healthy volunteer blood donors) 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. * Age greater than 18 years; hemoglobin greater than or equal to 12 g/dL; no history of bleeding problems; not taking aspirin or any medication that may affect erythrocyte biochemistry * Willingness to sign the healthy volunteer informed consent form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 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. |
| 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. |
| 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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) | Date treatment consent signed to date off study, an average of 115 days. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Solid Tumor Dose Level 1 Methoxyamine (TRC102) 125mg & Temozolomide 75mg/m^2 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. | 3 |
| 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) 125mg/m\^2 PO QD on days 1-5. | 6 |
| Phase 1 Solid Tumor Dose Level 3 Methoxyamine (TRC102) 50mg & Temozolomide 150mg/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. | 4 |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & 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. | 8 |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & 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. | 3 |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & 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. | 10 |
| 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) 150mg/m\^2 PO QD on days 1-5. | 15 |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/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. | 3 |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) 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. | 16 |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) 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. | 16 |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) 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. | 9 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Phase I Dose Escalation | Declined to participate (before treatment started) | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1 Solid Tumor Dose Level 2 Methoxyamine (TRC102) 50mg & Temozolomide 125mg/m^2 | Phase 1 Solid Tumor Dose Level 3 Methoxyamine (TRC102) 50mg & Temozolomide 150mg/m^2 | Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/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) | Phase 1 Solid Tumor Dose Level 1 Methoxyamine (TRC102) 125mg & Temozolomide 75mg/m^2 | Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 5 Participants | 0 Participants | 8 Participants | 8 Participants | 1 Participants | 1 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 2 Participants | 7 Participants | 3 Participants | 7 Participants | 10 Participants | 3 Participants | 8 Participants | 8 Participants | 2 Participants | 8 Participants | 63 Participants |
| Age, Continuous | 57.82 years STANDARD_DEVIATION 6.83 | 62.9 years STANDARD_DEVIATION 14.03 | 58.54 years STANDARD_DEVIATION 5.37 | 48.57 years STANDARD_DEVIATION 11.52 | 58.44 years STANDARD_DEVIATION 10.45 | 61.51 years STANDARD_DEVIATION 11.25 | 57 years STANDARD_DEVIATION 5.91 | 62.24 years STANDARD_DEVIATION 10.75 | 61.97 years STANDARD_DEVIATION 14.1 | 59.13 years STANDARD_DEVIATION 12.22 | 49.14 years STANDARD_DEVIATION 18.4 | 59.11 years STANDARD_DEVIATION 12.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 8 Participants | 3 Participants | 7 Participants | 13 Participants | 3 Participants | 15 Participants | 14 Participants | 3 Participants | 9 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 7 Participants | 3 Participants | 6 Participants | 10 Participants | 3 Participants | 14 Participants | 10 Participants | 2 Participants | 8 Participants | 68 Participants |
| Region of Enrollment United States | 6 participants | 4 participants | 8 participants | 3 participants | 10 participants | 15 participants | 3 participants | 16 participants | 16 participants | 3 participants | 9 participants | 93 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants | 2 Participants | 5 Participants | 6 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants | 9 Participants | 43 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 4 Participants | 1 Participants | 5 Participants | 9 Participants | 1 Participants | 11 Participants | 12 Participants | 1 Participants | 0 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 4 | 0 / 7 | 0 / 3 | 2 / 10 | 2 / 15 | 0 / 3 | 1 / 16 | 0 / 16 | 1 / 9 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 4 / 4 | 7 / 7 | 3 / 3 | 10 / 10 | 15 / 15 | 3 / 3 | 16 / 16 | 16 / 16 | 9 / 9 |
| serious Total, serious adverse events | 1 / 3 | 3 / 6 | 2 / 4 | 1 / 7 | 1 / 3 | 4 / 10 | 9 / 15 | 2 / 3 | 9 / 16 | 9 / 16 | 2 / 9 |
Outcome results
Primary
Phase 1 Maximum Tolerated Dose (MTD) of Oral Temozolomide (TMZ) in Participants With Refractory Solid Tumors.
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.
Time frame: First cycle of treatment; approximately 28 days
Population: 51/52 participants were analyzed in phase 1 because one participant declined to participate (before treatment started).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 1 Maximum Tolerated Dose (MTD) of Oral Temozolomide (TMZ) in Participants With Refractory Solid Tumors. | 150 mg/m^2 |
Primary
Phase 1 Maximum Tolerated Dose (MTD) of Oral TRC102 in Participants With Refractory Solid Tumors.
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.
Time frame: First cycle of treatment; approximately 28 days
Population: 51/52 participants were analyzed in phase 1 because one participant declined to participate (before treatment started).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 1 Maximum Tolerated Dose (MTD) of Oral TRC102 in Participants With Refractory Solid Tumors. | 125 mg |
Primary
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)
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.
Time frame: First 5 days of treatment
Population: 51/52 participants were analyzed for plasma PK in phase 1 because one participant declined to participate (before treatment started).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | 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) | 0.75 Micromolar (µM) | Standard Deviation 0.49 |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | 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) | 1.49 Micromolar (µM) | Standard Deviation 1.07 |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | 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) | 0.97 Micromolar (µM) | Standard Deviation 0.27 |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | 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) | 2.36 Micromolar (µM) | Standard Deviation 2.68 |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | 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) | 3.51 Micromolar (µM) | Standard Deviation 2.52 |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | 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) | 7.11 Micromolar (µM) | Standard Deviation 8.21 |
| Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | 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) | 7.45 Micromolar (µM) | Standard Deviation 5.39 |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2 | 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) | 7.54 Micromolar (µM) | Standard Deviation 5.4 |
Primary
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)
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.
Time frame: First day of treatment
Population: 51/52 participants were analyzed for urine PK in phase 1 because one participant declined to participate (before treatment started).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | 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) | 1.6 Percentage | Standard Deviation 1.2 |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | 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) | 0.8 Percentage | Standard Deviation 0.3 |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | 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) | 0.8 Percentage | Standard Deviation 0.5 |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | 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) | 2.5 Percentage | Standard Deviation 2.9 |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | 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) | 4.0 Percentage | Standard Deviation 3.1 |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | 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) | 4.8 Percentage | Standard Deviation 5.2 |
| Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | 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) | 4.1 Percentage | Standard Deviation 4.6 |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2 | 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) | 3.8 Percentage | Standard Deviation 2.3 |
Primary
Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer
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.
Time frame: Response rate at one year
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Partial Response | 1 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Death on Study | 1 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Progressive Disease | 8 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Complete Response | 0 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Refusing Further Treatment | 1 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Clinical Progression | 2 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Stable Disease | 3 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Progressive Disease | 3 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Complete Response | 0 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Partial Response | 0 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Stable Disease | 10 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Death on Study | 0 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Clinical Progression | 2 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Refusing Further Treatment | 1 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Death on Study | 0 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Partial Response | 0 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Refusing Further Treatment | 1 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Not Assessed Due to Clinical Progression | 1 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Progressive Disease | 2 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Stable Disease | 5 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | Phase 2: Response Rate of This Combination in Participants With Colon Cancer, Non-small Cell Lung Cancer (NSCLC), and Granulosa Cell Ovarian Cancer | Complete Response | 0 Participants |
Primary
The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ
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.
Time frame: At dose-limiting toxicity (DLT) determined in the first cycle; approximately 28 days
Population: 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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 0 Dose limiting toxicities |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 0 Dose limiting toxicities |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 0 Dose limiting toxicities |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 0 Dose limiting toxicities |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 1 Dose limiting toxicities |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 0 Dose limiting toxicities |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 0 Dose limiting toxicities |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 0 Dose limiting toxicities |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 1 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 1 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 0 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Thrombocytopenia | 1 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | Grade 4 Neutropenia | 1 Dose limiting toxicities |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2 | The Number of Dose Limiting Toxicities Observed in Participants Receiving Oral TRC102 in Combination With Oral TMZ | A Drop in Hemoglobin (Hgb) ≥3.0 g/dL Over One Week | 2 Dose limiting toxicities |
Secondary
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
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.
Time frame: Duration on study, an average of 130 days
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | 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 | 1.97 Months |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | 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 | 3.02 Months |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | 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 | 5.52 Months |
Other Pre-specified
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)
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.
Time frame: Date treatment consent signed to date off study, an average of 115 days.
Population: 92/93 participants were analyzed because one participant in phase 1 dose level 3 declined to participate (before treatment started).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | 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) | 3.0 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | 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) | 6 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | 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) | 4 Participants |
| Phase 1 Solid Tumor Dose Level 4 Methoxyamine (TRC102) 75mg & Temozolomide 150mg/m^2 | 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) | 7 Participants |
| Phase 1 Solid Tumor Dose Level 5 Methoxyamine (TRC102) 100mg & Temozolomide 150mg/m^2 | 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) | 3 Participants |
| Phase 1 Solid Tumor Dose Level 6 Methoxyamine (TRC102) 125mg & Temozolomide 150mg/m^2 | 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) | 10 Participants |
| Phase 1 Solid Tumor Dose Level 7 Methoxyamine (TRC102) 150mg & Temozolomide 150mg/m^2 | 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) | 15 Participants |
| Phase 1 Solid Tumor Dose Level 8 Methoxyamine (TRC102) 150mg & Temozolomide 200mg/m^2 | 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) | 3 Participants |
| Ph 2 Colorectal Cancer TMZ 150mg/m^2/Methoxyamine 125mgOR100mg(Based on Body Surface Area) | 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) | 16 Participants |
| Ph2 Non Small Cell Lung Cancer TMZ 150mg/m^2/Methoxyamine125mgOR100mg(Based on Body Surface Area) | 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) | 16 Participants |
| Ph 2 Granulosa Cell Temozolomide 150mg/m^2 & Methoxyamine 125mgOR 100mg (Based on Body Surface Area) | 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) | 9 Participants |