A Multiple Dose, Dose Escalation Trial of AEB1102 in Patients With Advanced Solid Tumors

Phase 1

Completed

Brief Summary: This is the first-in-human study of the safety of increasing dose levels of AEB1102 in patients with advanced cancers. The study will also evaluate the amounts of AEB1102 in blood, the effects of AEB1102 on blood amino acid levels and tumor growth.

Detailed Description: In this phase I/2 multiple dose, dose escalation study utilizing a classic 3+3 design. Sequential cohorts of patients will receive AEB1102 IV weekly at one of a series of increasing dose levels. Dose escalation will be dependent on the frequency of specific dose-limiting toxicities in the prior cohort of patients. The study will determine the maximum tolerated dose (MTD) of AEB1102, evaluate the safety profile of the compound, assess the pharmacokinetic profile of AEB1102, determine the effect of AEB1102 on blood arginine levels and evaluate the anti-tumor activity of AEB1102.

Following the determination of the MTD, additional cohorts of patients with uveal, cutaneous melanoma and small cell lung cancer will be enrolled and treated with AEB1102 at the MTD.

Recruitment & Eligibility

Inclusion Criteria

For patients participating in any part of the trial:

has an advanced solid tumor previously treated with, or inability to tolerate, standard therapy for the disease, or for which a standard therapy does not exist, and as such is considered a candidate for Phase 1 treatment
has adequate organ function: Hgb ≥9 g/dL; absolute neutrophil count (ANC) ≥ 1.5x109/L; plt ≥ 100,000/μL; AST and ALT < 2.5x ULN (< 5x ULN in patients with liver metastases); total bilirubin < 2.0 mg/dL; serum creatinine ≤ 1.5x ULN
ECOG performance score 0-2

For patients participating in any expansion group:

has measurable disease based on RECIST 1.1 as determined by the treating investigator. Tumor lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
willing to consent for biopsy is strongly recommended but not mandatory
recovery of toxicities related to any prior treatments to at least Grade 1 by CTCAE v 4.03. Exceptions are patients with adverse event(s) that are clinically nonsignificant and/or stable on supportive therapy.

For patients participating in specific expansion groups:

Cutaneous Melanoma:

unresectable, locally advanced or metastatic (AJCC stage IIIB, IIIC, or IV) cutaneous malignant melanoma
relapsed or progressive disease after or unable to tolerate at least one prior systemic anticancer regimen for metastatic disease involving immunotherapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4)
in tumors with a relevant BRAF mutation, relapsed, refactory, or unable to tolerate at least one prior systemic anticancer regimen for metastic disease involving a BRAF inhibitor

Uveal Melanoma:

Small Cell Lung Cancer:

extensive disease previously treated with, or inability to tolerate, platinum-based chemotherapy

Exclusion Criteria

has primary CNS malignancy
history of untreated brain mets or leptomeningeal disease or spinal cord compression
effects of prior anticancer therapy recovered to grade < 2
known HIV
active infection
major surgery within 2 weeks
history of another malignancy within 2 years prior

Arm && Interventions

Group	Intervention	Description
AEB1102 Dose Escalation Cohort 3	Co-ArgI-PEG	4 patients dosed at 0.04 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 4	Co-ArgI-PEG	4 patients dosed at 0.08 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 8	Co-ArgI-PEG	7 patients dosed at 0.40 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 1	Co-ArgI-PEG	3 patients dosed at 0.01 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 2	Co-ArgI-PEG	4 patients dosed at 0.02 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 5	Co-ArgI-PEG	3 patients dosed at 0.12 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 6	Co-ArgI-PEG	4 patients dosed at 0.18 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 7	Co-ArgI-PEG	5 patients dosed at 0.27 mg/kg until MTD determined
AEB1102 Dose Escalation Cohort 9	Co-ArgI-PEG	7 patients dosed at 0.33 mg/kg until MTD determined MTD determined at 0.33 mg/kg
AEB1102 Expansion	Co-ArgI-PEG	Uveal: 11 patients dosed at 0.33 mg/kg Cutaneous Melanoma: 11 dosed at 0.33 mg/kg SCLC: 13 patients dosed at 0.33 mg/kg

Primary Outcome Measures

Name	Time	Method
maximum tolerated dose	4 weeks	the dose level at which no more than 1/6 patients experiences dose-limiting toxicity

Secondary Outcome Measures

Name	Time	Method
safety profile (changes in physical exam, laboratory measures, reported adverse events)	4 weeks +	changes in physical exam, laboratory measures, reported adverse events

Locations (11): Massachusetts General
🇺🇸
Boston, Massachusetts, United States
Providence Cancer Center
🇺🇸
Portland, Oregon, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
UCLA
🇺🇸
Los Angeles, California, United States
Washington University
🇺🇸
Saint Louis, Missouri, United States
Columbia University
🇺🇸
New York, New York, United States
University of Colorado
🇺🇸
Aurora, Colorado, United States
Research Center: Mid Florida Hematology/Oncology Centers
🇺🇸
Orange City, Florida, United States
Pinnacle Research
🇺🇸
Phoenix, Arizona, United States
Dana Farber
🇺🇸
Boston, Massachusetts, United States
UTSW
🇺🇸
Dallas, Texas, United States