This is a Phase I, First-In-Human, open label, dose escalation study to evaluate the safety,
tolerability, and pharmacokinetics of ABM-1310. A "3+3" design will be used to determine MTD
and RP2D.
This is a first-in-human, phase I clinical study with ABM-1310, an investigational, oral,
small molecule B-Raf inhibitor in patients with documented BRAF V600 mutation and locally
advanced or metastatic solid tumors such as melanoma, colorectal cancer, glioblastoma,
cholangiocarcinoma, non-small cell lung cancer, thyroid cancer, or ovarian carcinoma who have
no effective standard treatment options available. The primary objective of this study is to
determine the Maximum Tolerated Dose (MTD) and/or the Recommended Phase II Dose (RP2D).
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.
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.
Inclusion Criteria:
1. Male and female subjects age 18 years and older who are able to sign informed consent
and to comply with the protocol
2. Patients with histologically or cytologically-documented, locally advanced, or
metastatic solid malignancy that has either (a) failed prior standard 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.
- Documentation of positive BRAF V600E mutation, or any other B-Raf V600 mutation
is required for enrollment.
- Patients with active brain metastasis are not eligible for enrollment
- Patients with asymptomatic or stable brain metastasis are allowed for enrollment
if there is strong scientific rationale for likelihood of benefit on the basis of
molecular pathways per PI's judgment and discussed with SMC (Modernizing Clinical
Trial Eligibility Criteria: Recommendations of the American Society of Clinical
Oncology-Friends of Cancer Research Brain Metastases Working Group 2017).
- Stable brain metastasis is defined as patients are on a stable (unchanged)
dose of corticosteroids for more than one month, or patients are off
corticosteroid for at least 2 weeks. (Investigators are encouraged to
communicate with the medical monitor case by case for those
steroids-dependent patients with brain metastases.)
3. Must have at least one measurable lesion as defined by RECIST V1.1 criteria for solid
tumors
4. ECOG performance status of 0 or 1
5. Adequate organ function confirmed at screening and within 28 days of initiating
treatment, as evidenced by:
1. Absolute Neutrophil Count (ANC) ≥ 1.0 x 10^9/L
2. Hemoglobin (Hgb) ≥ 9 g/dl
3. Platelets (Plt) ≥ 100 x 10^9/L
4. AST/ALT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases
are present
5. Total bilirubin ≤ 1.5 x ULN, or direct bilirubin <ULN for patients with total
bilirubin levels >1.5 ULN
6. Serum creatinine <1.5 x ULN or measured or calculated (per institutional
standard) creatinine clearance of > 60 mL/min.
6. Negative pregnancy test within 72 hours before starting study treatment in all
pre-menopausal women and women <12 months after the onset of menopause
7. Male and female subjects must agree to take sufficient contraceptive methods to avoid
pregnancy before first dose of study treatment, during the study, and for at least 60
days after ceasing study treatment
Exclusion Criteria:
1. Women who are pregnant or breast-feeding
2. Women of child-bearing potential (WOCBP) who does not use adequate birth control
3. Patients with any hematologic malignancy. This includes leukemia (any form), lymphoma,
and multiple myeloma
4. Have a second primary malignancy that, in the judgment of the investigator, may affect
the interpretation of results
5. Patients with
1. A history of primary central nervous system tumors or
2. Carcinomatous meningitis
6. Patients with history of stroke ≤ 6 months prior to starting study drug
7. Impaired cardiac function or clinically significant cardiac diseases, including but
not limited to any of the following:
1. Left Ventricular Ejection Fraction (LVEF) < 45% as determined by MUGA scan or
ECHO
2. Congenital long QT syndrome
3. QTcF ≥ 450 msec (mean) on screening (Triplicate 12-Lead ECG)
4. Unstable angina pectoris ≤ 6 months prior to starting study drug
5. Acute myocardial infarction ≤ 6 months prior to starting study drug
6. Use of pacemaker
8. Patients with
1. Unresolved diarrhea ≥ CTCAE Grade 2, or
2. Impairment of gastrointestinal (GI) function, or
3. GI disease or conditions that may significantly alter the absorption of ABM-1310
(e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, or small bowel resection)
9. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
uncontrolled hypertriglyceridemia [triglycerides >500 mg/dL], active or uncontrolled
infection) that could cause unacceptable safety risks or compromise compliance with
the protocol
10. Extensive prior radiotherapy to more than 30% of bone marrow reserves, or prior bone
marrow/stem cell transplantation within 5 years
11. Patients who have received chemotherapy, targeted therapy or immunotherapy ≤ 4 weeks
(6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not
recovered from side effects of such therapy
12. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy
13. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy
14. Patients who are currently receiving treatment with therapeutic doses of warfarin
sodium or any other coumarin-derivative anticoagulants
15. Patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study
drug or who have not recovered from the side effects of such treatment
16. Patients who are currently receiving treatment with medication that has known risk to
prolong the QT interval, and the treatment cannot either be discontinued or switched
to a different medication prior to starting study drug
17. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory; patients with well controlled HIV might be enrolled per investigator's
discretion)
18. Known history of active infection with Hepatitis B (e.g., HBsAg reactive), or
Hepatitis C (e.g., HCV RNA (qualitative) is detected)
19. History of alcohol or drug abuse ≤ 3 months prior to first dose
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that, in the opinion of the investigator, might confound the results of the trial,
interfere with the patient's participation and compliance in the trial