A Phase I, Open-Label, Multicenter, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-Cancer Activity of ABM-1310 in Patients With BRAF V600-Mutant Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- ABM-1310
- Conditions
- Advanced Solid Tumor
- Sponsor
- ABM Therapeutics Shanghai Company Limited
- Enrollment
- 20
- Locations
- 10
- Primary Endpoint
- Number of participants with abnormal vital signs
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is a Phase I, Open-Label, Multicenter, Dose Escalation and Expansion Study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-cancer activity of ABM-1310 in patients with BRAF V600-Mutant advanced solid tumors. This study consists of two stages: dose escalation and dose expansion. During the dose escalation stage, a classic "3+3" design will be used to guide dose escalation to determine MTD and RP2D. The dose expansion stage will be initiated at the MTD or the optimal dose determined by the Safety Monitoring Committee (SMC ) as a fixed dose level (MTD or the optimal dose needs to be reviewed by the SMC and subjects are safe and tolerable at that dose level).
Detailed Description
This is a Phase I, Open-Label, Multicenter, Dose Escalation and Expansion Study to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-cancer activity of ABM-1310 in patients with BRAF V600-Mutant advanced solid tumors. The primary objective of this study is to evaluate the safety and tolerability of ABM-1310 monotherapy, and to determine MTD and RP2D. The study will be conducted in two stages: Dose escalation stage: The dose escalation will be guided by a "3+3" design. In this study, the actual dose escalation will be based on a priming dose one level below the highest safe dose or two levels below the MTD that has been tested in US clinical trials when the enrolment of the China study actually initiates, and subsequent escalated doses may be adjusted as appropriate (e.g., the escalated doses following 150 mg BID in the China study may be adjusted to 200 mg BID, 250 mg BID and 300 mg BID. The actual priming dose and subsequent escalated doses for the China study are determined by the SMC). Dose expansion stage: Subjects will begin to receive oral doses of ABM-1310, BID, for 28-day cycles at a fixed dose level (as determined at the dose escalation stage).The dose expansion stage is expected to include the following two cohorts of advanced solid tumors with BRAF V600 mutations: Cohort 1: primary extracranial solid tumors, subjects with BMs preferentially enrolled, up to 15 patients per tumor type; Cohort 2: primary intracranial solid tumors, N = up to 30 patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects who are able to understand and voluntarily sign informed consent forms (ICFs).
- •Male and female subjects at the age of ≥18 and ≤80 at the time of screening.
- •Patients with histologically or cytologically-confirmed, locally advanced, or metastatic solid tumors with (a) failure of prior standard therapy, (b) no standard therapy available, or (c) for whom standard therapy is not applicable considered by the patient or treating physician. There is no limit to the number of prior treatment lines. Subjects who were previously treated with BRAF and/or MEK inhibitors are allowed to be enrolled in this study.
- •Documentation of positive BRAF V600 mutation is required for enrollment (the blood BRAF V600 test report is received at the dose-escalation stage). Representative tumor specimens suitable for confirmation of BRAF V600 mutations by retrospective analysis are required (for dose-expansion stage only). It is recommended to provide sufficient fresh/archived tumor tissue samples (formalin-fixed paraffin-embedded tumor specimens \[preferred\]) or 5-10 available unstained sections of good quality for verification of BRAF V600 mutation status at the central laboratory. For any subject who is unable to provide suitable and adequate tumor specimens, re-biopsy (with controllable safety) can be performed in a non-mandatory manner if it is feasible as assessed by the investigator and the subject gives informed consent; if re-biopsy is impossible or refused by the subject, his/her eligibility for enrollment shall be confirmed by both the investigator and the sponsor.
- •Patients with BMs/primary intracranial solid tumors that are asymptomatic, or that are symptomatic but on a stable or decreasing dose of steroids for at least 2 weeks are eligible for enrollment. The specific criteria are as follows:
- •Subjects with inactive and asymptomatic BMs/primary intracranial solid tumors;
- •Subjects who have active, mild neurological signs and symptoms currently requiring no therapy with steroids, and have no history of epileptic seizure within 2 weeks prior to initiation of treatment;
- •Subjects who have active, neurological signs and symptoms and were on a stable or gradually reducing dose up to 4 mg of dexamethasone (or equivalent) per day within 2 weeks prior to initiation of treatment;
- •Subjects who only have evaluable lesions are allowed to be included for the dose escalation stage. They must have at least one measurable lesion (intracranial or extracranial) as defined by RECIST V1.1 criteria or modified RECIST v1.1 for subjects with BMs or the RANO criteria for subjects with primary intracranial solid tumors during screening at the dose expansion stage. Lesions previously treated with radiotherapy shall not be deemed as target lesions unless significant progression as shown on imaging.
- •o For BMs from solid tumors;At least one measurable extracranial lesion is required if the longest diameter of the intracranial lesion is less than 0.5 cm (for dose expansion stage only).Subjects with measurable intracranial lesions of 0.5-3 cm in longest diameter (the lower limit of the longest diameter is defined according to the modified RECIST V1.1 criteria are allowed for the study, and measurable extracranial lesions are not required.Subjects with intracranial lesions \> 3 cm in longest diameter are not eligible for the study.
Exclusion Criteria
- •Women who are pregnant or breast-feeding.
- •Subjects with history of neoplasm malignant within 5 years prior to screening, excluding cured carcinoma in situ of cervix, non-melanoma skin cancer, localized prostate cancer and other tumors/cancers that have undergone radical treatment and shown no signs of disease for at least 3 years (This exclusion criterion is only applicable for dose expansion stage. For the dose escalation stage, any patient with double primary malignant solid tumors who can indeed benefit from this study as confirmed by the investigator is eligible for the screening; however, those with any combined primary hematological malignant tumor shall be excluded).
- •Subjects with intracranial hypertension or associated risks (e.g., intracranial infection, intracranial hemorrhage).
- •Subjects with clinically uncontrolled pleural effusion, pericardial effusion, or ascites who, in the judgement of the investigator, are not eligible for enrollment.
- •Subjects with cancerous meningitis (leptomeningeal disease \[LMD\]).
- •Subjects with history of symptomatic stroke within 6 months prior to initiation of study treatment.
- •Subjects with epileptic seizure within 14 days prior to initiation of study treatment.
- •Impaired cardiac function or clinically significant cardiovascular disorder, including but not limited to any of the following:
- •Left Ventricular Ejection Fraction (LVEF) \< 50% as determined via cardiac ultrasound.
- •Long QT syndrome congenital.
Arms & Interventions
Monotherapy Dose Escalation and Dose Expansion
In US studies, dose escalation started at a 25 mg BID dose and subsequent dose-escalation groups included: 50 mg BID, 100 mg BID, 150 mg BID, 225 mg BID and 325 mg BID. In this study, the actual dose escalation will be based on a priming dose one level below the highest safe dose or two levels below the MTD that has been tested in US clinical trials when the enrolment of the China study actually initiates, and subsequent escalated doses may be adjusted as appropriate (e.g., the escalated doses following 150 mg BID in the China study may be adjusted to 200 mg BID, 250 mg BID and 300 mg BID. The actual priming dose and subsequent escalated doses for the China study are determined by the SMC) The dose expansion stage in this study will be initiated at the MTD or the optimal dose determined by the SMC as a fixed dose level (MTD or the optimal dose needs to be reviewed by the SMC and subjects are safe and tolerable at that dose level).
Intervention: ABM-1310
Outcomes
Primary Outcomes
Number of participants with abnormal vital signs
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Number of participants with abnormal physical examinations
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Number of participants with abnormal ophthalmic evaluation
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Number of participants with abnormal ECG
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Number of participants with abnormal ECOG
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Number of participants with abnormal Karnofsky PS
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Maximum Tolerated Dose (MTD)
Time Frame: From the enrollment of subjects to the end of Cycle 1 (each cycle is 28 days) or up to treatment discontinuation, whichever occurs first, assessed up to 33 days.
MTD is defined as the highest dose level at which DLT is observed in ≤ 1/6 subjects at one single dose group
Recommended Phase 2 Dose (RP2D)
Time Frame: From the enrollment of subjects to the end of Cycle 1 (each cycle is 28 days) or up to treatment discontinuation, whichever occurs first, assessed up to 33 days.
RP2D will be a dose either below or equal to MTD
Dose Limiting Toxicity (DLT)
Time Frame: Single dose PK observation period (5 days) and Cycle 1 (28 days) (33 days in total)
DLT will be evaluated according to NCI-CTCAE V5.0 criteria
The incidence of treatment-related adverse events AE(s)
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Number of participants with abnormal laboratory values
Time Frame: Up to 28 days from treatment discontinuation
Safety and tolerability of ABM-1310 monotherapy
Secondary Outcomes
- Area under the concentration time curve (AUC)(Up to Day 1, Day 8, Day 15, Day 22 and Day 28 of Cycle 1. Up to Day 1 and Day 2 of Cycle2. After Cycle2, tests every 2 cycles (each cycle is 28 days))
- Maximum plasma concentration (Cmax)(Up to Day 1, Day 8, Day 15, Day 22 and Day 28 of Cycle 1. Up to Day 1 and Day 2 of Cycle2. After Cycle2, tests every 2 cycles (each cycle is 28 days))
- Duration of Response (DOR)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Time to maximum plasma concentration (Tmax)(Up to Day 1, Day 8, Day 15, Day 22 and Day 28 of Cycle 1. Up to Day 1 and Day 2 of Cycle2. After Cycle2, tests every 2 cycles (each cycle is 28 days))
- Half-life (T1/2)(Up to Day 1, Day 8, Day 15, Day 22 and Day 28 of Cycle 1. Up to Day 1 and Day 2 of Cycle2. After Cycle2, tests every 2 cycles (each cycle is 28 days))
- Apparent plasma clearance (CL/F)(Up to Day 1, Day 8, Day 15, Day 22 and Day 28 of Cycle 1. Up to Day 1 and Day 2 of Cycle2. After Cycle2, tests every 2 cycles (each cycle is 28 days))
- Apparent volume of distribution (Vz/F)(Up to Day 1, Day 8, Day 15, Day 22 and Day 28 of Cycle 1. Up to Day 1 and Day 2 of Cycle2. After Cycle2, tests every 2 cycles (each cycle is 28 days))
- Objective Response Rate (ORR)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Disease Control Rate (DCR)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Progression free survival (PFS)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Intracranial Objective Response Rate (ORR)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Intracranial Disease Control Rate (DCR)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Intracranial Duration of Response (DOR)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Intracranial Progression free survival (PFS)(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Deepness of Response（DPR）(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)
- Intracranial Deepness of Response（DPR）(From the enrollment of subjects to the time of disease progression in radiological imaging or death from any cause, whichever occurs first, assessed approximately 12 months.)