Clinical trial NCT02628574: Phase 1 Open-label Study of TRX518 Monotherapy and TRX518 in Combination With Gemcitabine, Pembrolizumab, or Nivolumab
Official title: A Phase 1 Study of TRX518 Monotherapy and TRX518 in Combination With Gemcitabine, Pembrolizumab, or Nivolumab in Adults With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Keywords: Metastatic
Stage III or IV
recurrent
refractory
solid tumors
Lead sponsor: Leap Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2015-12-11
Enrollment: 109
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will be conducted in 5 parts (Parts A, B, C, D and E).

Monotherapy Treatment:

Subjects ≥18 years with advanced solid tumors will be enrolled in the study. Monotherapy dose escalation will be performed in Part A. Cycle 1 data from each cohort will be evaluated for safety and dose-limiting toxicities (DLTs) prior to dose escalation. Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a patient is enrolled and cohorts will be dosed consecutively by ascending dose. Once the maximum tolerated dose (MTD) or maximum administered dose (MAD) has been identified, an expanded cohort will be enrolled (Part B).

Combination Treatment:

Subjects ≥18 years with advanced solid tumors will be enrolled in the study. Subjects will receive TRX518 in combination with gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E). Dose escalation will be performed for each part (Part Cesc, Part Desc, Part Eesc) and Cycle 1 data from each cohort will be evaluated for safety and dose-limiting toxicities (DLTs) prior to dose escalation. Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a patient is enrolled and cohorts will be dosed consecutively by ascending dose. Once the maximum tolerated dose (MTD) or maximum administered dose (MAD) has been identified, an expanded cohort will be enrolled (Part Cexp, Part Dexp, Part Eexp).


Eligibility criteria: Inclusion Criteria:

* Advanced Solid Malignancies: Histologically documented metastatic or locally advanced, incurable solid malignancy (Parts A and B); histologically documented metastatic or locally advanced, incurable solid malignancy for which gemcitabine is clinically appropriate (e.g., non-small cell lung, breast, ovarian, pancreatic, and renal cancer); histologically documented metastatic or locally advanced, incurable solid malignancy for which pembrolizumab (Part D) or nivolumab (Part E) is approved. NOTE: Parts D and E only: Subject has either (1) received treatment with pembrolizumab or nivolumab for ≥4 months with a best response of stable disease and plans to continue treatment with either pembrolizumab or nivolumab in accordance with package insert; or (2) is not currently taking, but is eligible for treatment with, pembrolizumab or nivolumab in accordance with the approved indications for each as referenced in the package insert.
* Expected survival of at least 12 weeks after dosing.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
* Evidence of adequate organ function by standard laboratory tests.
* All female subjects of child bearing age must be either surgically sterile, postmenopausal for at least 1 year, or using an acceptable method of contraception. Adequate contraception for both male and female subjects must be used from the beginning of the screening period until at least 8 weeks after the last dose of study drug.

Exclusion Criteria:

* Hematologic malignancies or multiple myeloma.
* Known, clinically important cardiac or respiratory disease
* Any concomitant serious physical illness other than cancer (e.g., immune deficiency disease, bleeding disorder, etc.) within 1 year prior to dosing. No history of autoimmune disease.
* Active, uncontrolled infections within 7 days of study entry requiring systemic therapy.
* Evidence of progression of central nervous system (CNS) metastases or symptomatic CNS metastases within 30 days prior to dosing.
* History of known or suspected autoimmune disease with the specific exceptions of vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment. (Parts C, D and E only).
* Clinically-significant gastrointestinal disorders, such as perforation, gastrointestinal bleeding, or diverticulitis (Parts D and E only).
* Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment (Parts D and E only).
* History of (non-infectious) pneumonitis that required steroids or current pneumonitis (Parts D and E only).
* History of interstitial lung disease (Parts D and E only).

Primary outcomes:
measure: Adverse events
timeFrame: through 30 days post last dose
Secondary outcomes:
measure: TRX518 peak concentration (Cmax)
timeFrame: various timepoints through 1 week post dose
measure: Time to peak concentration (Tmax)
timeFrame: various timepoints through 1 week post dose
measure: Area under the curve (AUC)
timeFrame: various timepoints through 1 week post dose
measure: RECIST assessment for evidence of antitumor activity
timeFrame: up to 1 year
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center
state: New Mexico
city: Cleveland
country: United States
facility: University Hospitals
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
Study officials:
affiliation: Leap Therapeutics, Inc.
name: Cyndi Sirard, MD
role: STUDY_CHAIR
References:
citation: Zappasodi R, Sirard C, Li Y, Budhu S, Abu-Akeel M, Liu C, Yang X, Zhong H, Newman W, Qi J, Wong P, Schaer D, Koon H, Velcheti V, Hellmann MD, Postow MA, Callahan MK, Wolchok JD, Merghoub T. Rational design of anti-GITR-based combination immunotherapy. Nat Med. 2019 May;25(5):759-766. doi: 10.1038/s41591-019-0420-8. Epub 2019 Apr 29.