A Phase I, First-In-Human, Multicenter, Open-Label Dose Escalation and Dose Expansion Study of ABM-1310, as a Monotherapy and a Combination Therapy, Administered Orally in Adult Patients With Advanced Solid Tumors Harboring BRAF Mutations
Overview
- Phase
- Phase 1
- Intervention
- ABM-1310
- Conditions
- Advanced Solid Tumor
- Sponsor
- ABM Therapeutics Corporation
- Enrollment
- 53
- Locations
- 8
- Primary Endpoint
- Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is a Phase I, First-In-Human, open label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-cancer activity of ABM-1310 in adult patients with locally advanced or metastatic solid tumors who have no effective standard treatment options available, as monotherapy in patients with documented BRAF V600 mutation, or in combination with cobimetinib (Cotellic®) in adult patients who have documented BRAF mutation and progressive disease or intolerance to at least one prior line of systemic therapy.
Detailed Description
This is a Phase I, First-In-Human, open label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-cancer activity of ABM-1310 in adult patients with locally advanced or metastatic solid tumors who have no effective standard treatment options available, as monotherapy in patients with documented BRAF V600 mutation, or in combination with cobimetinib (Cotellic®) in adult patients who have documented BRAF mutation and progressive disease or intolerance to at least one prior line of systemic therapy. The primary objectives of this study are to determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase II Dose (RP2D) of both single agent and combination treatment and to assess the safety and tolerability of ABM-1310 as a monotherapy and in combination. Study consists of three Parts: Part A: The starting dose of ABM-1310 is 25 mg po bid, and dose escalation will be guided by a "3+3" design. ABM-1310 will be administered twice daily on a continuous schedule. Each treatment cycle consists of 28 days. Part B: The starting dose of ABM-1310 will be a dose below the MTD that has been demonstrated to be safe in Part A Monotherapy. A classic "3+3" design will guide the dose escalation. At each dose level, ABM-1310 will be administered in combination with 60 mg cobimetinib (Cotellic ®) once daily (qd) for the first 21 days of each 28-day treatment cycle. Part C: * In C-1 (Monotherapy - Primary CNS Tumors) and C-2 (Monotherapy - Advanced or Metastatic solid tumors excluding Primary CNS tumors with or without Brain Metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part A until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met. * In C-3 (Combination therapy - Advanced/Metastatic Solid Tumors including Primary CNS Tumors but excluding Melanoma with Brain Metastsis) and C-4 (Combination therapy - Melanoma with Brain Metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part B, in combination with cobimetinib (Cotellic®) 60 mg administered the first 21 days of each 28-day treatment cycle until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met. Dose limiting toxicity (DLT) will be evaluated and managed per the pre-defined DLT criteria and rules specified in the protocol. MTD and/or RP2D will be confirmed in a dose confirmation cohort.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female subjects age 18 years and older who are able to sign informed consent and to comply with the protocol
- •Patients with histologically or cytologically-documented, locally advanced, or metastatic solid tumor malignancy that has either (a) progressed on at least one line of prior standard systemic therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the patient or treating physician. There is no limit to the number of prior treatment regimens
- •Part A: Patients with advanced or metastatic solid tumors with documentation of positive BRAF V600E mutation, or any other BRAF V600 mutation is required for enrollment
- •Part B: Patients with advanced or metastatic solid tumors with documentation of any BRAF mutation.
- •C-1: Patients with primary central nervous system (CNS) tumors and documentation of positive BRAF V600 mutation
- •C-2: Patients with advanced or metastatic solid tumors and documentation of positive BRAF V600 mutation excluding primary CNS tumor
- •C-3: Patients with advanced or metastatic solid tumors and documentation of positive BRAF mutation including primary CNS tumors but excluding melanoma with brain metastasis
- •C-4: Patients with melanoma with brain metastasis and documentation of positive BRAF mutation
- •Patients with active or stable brain metastasis that are asymptomatic, or that are symptomatic treated with a total daily dose of no more than 4 mg of dexamethasone (or equivalent) that is stable or tapering for at least 2 weeks prior to first treatment are eligible for enrollment. Patients with neurologic signs and symptoms who are not being treated with steroids are eligible and should have no experience of seizure within 2 weeks prior to first treatment.
- •Must have at least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors or the RANO criteria for primary CNS tumors, such as gliomas.
Exclusion Criteria
- •Women who are pregnant or breast-feeding
- •Women of child-bearing potential (WOCBP) who does not use adequate birth control
- •Patients with any hematologic malignancy. This includes leukemia, lymphoma, and multiple myeloma
- •Have a second primary malignancy that, in the judgment of the investigator, may affect the interpretation of results
- •Patients with carcinomatous meningitis (leptomeningeal disease (LMD))
- •Patients with history of stroke ≤ 6 months prior to starting study drug
- •Patients who have had an experience of seizure within 14 days prior to first treatment
- •Impaired cardiac function or clinically significant cardiac diseases, including but not limited to any of the following:
- •Left Ventricular Ejection Fraction (LVEF) \< 45% as determined by MUGA scan or ECHO
- •Congenital long QT syndrome
Arms & Interventions
Monotherapy Dose Escalation
A classic "3+3" design will be used to determine MTD and RP2D. Three to six patients per treatment cohort will be assigned to receive sequentially higher oral doses of ABM-1310 on a twice daily schedule (bid) for 28-day cycles, starting at a dose of 25 mg bid. Patients will receive twice daily oral doses of ABM-1310 continuously until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: ABM-1310
Combination Therapy Dose Escalation
A classic "3+3" design will guide the dose escalation in Part B. At each dose level, ABM-1310 will be administered in combination with cobimetinib (Cotellic ®) once daily (qd) for the first 21 days of each 28-day treatment cycle. The starting dose of ABM-1310 will be a dose below the MTD that has been demonstrated to be safe in Part A Monotherapy.
Intervention: ABM-1310
Combination Therapy Dose Escalation
A classic "3+3" design will guide the dose escalation in Part B. At each dose level, ABM-1310 will be administered in combination with cobimetinib (Cotellic ®) once daily (qd) for the first 21 days of each 28-day treatment cycle. The starting dose of ABM-1310 will be a dose below the MTD that has been demonstrated to be safe in Part A Monotherapy.
Intervention: Cobimetinib
Monotherapy Therapy Dose Expansion-1
- In C-1(Monotherapy - Primary CNS Tumors), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part A until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: ABM-1310
Monotherapy Therapy Dose Expansion-2
- In C-2 (Monotherapy - Advanced or Metastatic Solid Tumors excluding Primary CNS Tumor with or without Brain Metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part A until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: ABM-1310
Combination Therapy Dose Expansion-1
- In C-3 (Combination therapy - Advanced/Metastatic Solid Tumors including Primary CNS tumors but excluding Melanoma with Brain metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part B, in combination with cobimetinib (Cotellic®) 60 mg administered the first 21 days of each 28-day treatment cycle until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: ABM-1310
Combination Therapy Dose Expansion-1
- In C-3 (Combination therapy - Advanced/Metastatic Solid Tumors including Primary CNS tumors but excluding Melanoma with Brain metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part B, in combination with cobimetinib (Cotellic®) 60 mg administered the first 21 days of each 28-day treatment cycle until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: Cobimetinib
Combination Therapy Dose Expansion-2
- In C-4 (Combination therapy - Melanoma with Brain Metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part B, in combination with cobimetinib (Cotellic®) 60 mg administered the first 21 days of each 28-day treatment cycle until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: ABM-1310
Combination Therapy Dose Expansion-2
- In C-4 (Combination therapy - Melanoma with Brain Metastasis), continuous twice daily oral doses of ABM-1310 at the recommended phase 2 dose (RP2D) from Part B, in combination with cobimetinib (Cotellic®) 60 mg administered the first 21 days of each 28-day treatment cycle until disease progression, unacceptable toxicity, or a clinical observation satisfying another withdrawal criterion is met.
Intervention: Cobimetinib
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D)
Time Frame: End of Cycle 1 (each cycle is 28 days) or up to treatment discontinuation (an average of 6 months)
Determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) as a monotherapy and in combination therapy in Part A and Part B
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time Frame: Up to study discontinuation (an average of 1 year)
Safety and tolerability of ABM-1310 as a monotherapy and in combination therapy at Part A and Part B's Recommended Phase 2 dose (RP2D) in Part C
Number of participants with abnormal laboratory values
Time Frame: Up to study discontinuation (an average of 1 year)
Safety and tolerability of ABM-1310 as a monotherapy and in combination therapy at Part A and Part B's Recommended Phase 2 Dose (RP2D) in Part C
Secondary Outcomes
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0(Up to 30 days from treatment discontinuation)
- Number of participants with abnormal laboratory values(Up to 30 days from treatment discontinuation)
- Area under the concentration time curve (AUC)(Up to Day 1 of Cycle 2 (each cycle is 28 days))
- Maximum plasma concentration (Cmax)(Up to Day 1 of Cycle 2 (each cycle is 28 days))
- Steady-state concentration (Css)(Up to Day 1 of Cycle 2 (each cycle is 28 days))
- Time to maximum plasma concentration (Tmax)(Up to Day 1 of Cycle 2 (each cycle is 28 days))
- Half-life (T1/2)(Up to Day 1 of Cycle 2 (each cycle is 28 days))
- Objective Response Rate (ORR)(Up to study discontinuation (an average of 1 year))
- Disease Control Rate (DCR)(Up to study discontinuation (an average of 1 year))
- Duration of Response (DOR)(Up to study discontinuation (an average of 1 year))
- Progression free survival (PFS)(Up to study discontinuation (an average of 1 year))
- Overall Survival (OS)(Up to study discontinuation (an average of 1 year))
- Time to Response (TTR)(Up to study discontinuation (an average of 1 year))