Trial of TRX518 (Anti-GITR mAb) in Stage III or IV Malignant Melanoma or Other Solid Tumors (TRX518-001)

Study Description

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Brief Summary:

TRX518-001 is an open label, non-randomized single group assignment, Phase 1 single dose escalation study in adults with biopsy proven unresectable Stage III or Stage IV melanoma or other solid tumor malignancies.

Part A: The study objectives are to determine the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of TRX518 and to define the maximum tolerated dose at which there are tolerable side effects and/or maximum PK/PD parameter changes.

Subjects will be assigned to a cohort in the order screening is completed. Dose will depend upon the cohort in which a subject is enrolled and cohorts will be dosed consecutively by ascending dose. Part A has been completed.

Part B: A Dose-Escalation Study of Multi-dose TRX518 Monotherapy with objectives including characterization of the safety, tolerability, and pharmacokinetics, as well as, evaluate for evidence of anti-tumor activity and assess TRX518 immunogenicity.

Part C: An Expansion Cohort of Multi-dose TRX518 Monotherapy at the Maximum Tolerated Dose

Condition or disease	Intervention/treatment	Phase
Unresectable Stage III or Stage IV Malignant Melanoma or Other Solid Tumor Malignancies	Biological: TRX518	Phase 1

Detailed Description:

The following visits are required:

Part A:

• Screening visit: 1 to 2 appointments will be conducted to determine eligibility. All or most requirements can be determined from the patient's medical records.
• Baseline visit: within 7 days of the planned study dosing day a baseline physical exam, blood tests and electrocardiogram will be obtained.
• Dosing visit: 1 outpatient visit where TRX518 will be given IV over 1 hour followed by 4 hours of observation and some repeat blood tests.
• Follow up visits: 5 outpatient visits following dosing at 1, 8 and 15 days and 3, 6, 12, and 18 weeks post dosing
• Long term follow-up: 4 brief assessments by medical record review and/or telephone contact at 6, 12, 18, and 24 months post dosing.
• The core study duration is 18 weeks. The follow-up study duration is 24 months.

Parts B & C:

• Screening/Baseline visit: 1 appointment will be conducted to perform testing and evaluations for eligibility within 28 days of the first dosing day.
• Dosing Visits: Each subject will receive IV doses of TRX518 once every other week (e.g., D1 and D15) in 28-day cycles
• Follow up visits: When a patient stops treatment, they will enter the Follow-up Period and have an End of Treatment study visit approximately 30 days after the last dose of study drug. Subsequently, patients will have long-term follow-up approximately every 12 weeks until death or lost to follow up.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	71 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Part A: A First-in-Human Single Ascending Dose Study of TRX518 in Subjects With Unresectable Stage III or Stage IV Malignant Melanoma or Other Solid Tumor Malignancies Part B: A Dose-Escalation Study of Multi-dose TRX518 Monotherapy Part C: An Expansion Cohort of Multi-dose TRX518 Monotherapy at the Maximum Tolerated Dose
Study Start Date :	October 2010
Estimated Primary Completion Date :	October 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: TRX518	Biological: TRX518; Humanized, Fc disabled, anti-human GITR (glucocorticoid-induced tumor necrosis factor receptor) monoclonal antibody

Outcome Measures

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Primary Outcome Measures :

1. Part A: Adverse Events [ Time Frame: through 30 days post last dose ]
   Any adverse change in health or side effect from the initiation of the study drug dose through completion or premature withdrawal
2. Part A: TRX518 peak concentration (Cmax) [ Time Frame: various timepoints through 1 week post dose ]
   Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518
3. Part A: Time to peak concentration (Tmax) [ Time Frame: various timepoints through 1 week post dose ]
   Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518
4. Part A: Area under the curve (AUC) [ Time Frame: various timepoints through 1 week post dose ]
   Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518
5. Part A: Define a maximum single dose at which there are tolerable side effects and/or maximum PK/PcD parameter changes [ Time Frame: End of Cycle 1 (Day 28) ]
6. Parts B and C: Adverse Events [ Time Frame: through 30 days post dose ]
   Any adverse change in health or side effect from the initiation of the study drug dose through completion or premature withdrawal

Secondary Outcome Measures :

1. Part A: Evaluate the effect of TRX518 on lymphoid cell subset number and function [ Time Frame: At baseline and at various timepoints up to 6 weeks post dose ]
2. Part A: Assess TRX518 immunogenicity [ Time Frame: At baseline and at various timepoints up to 18 weeks post dose ]
3. Part A: Evaluate the effect of TRX518 on long-term safety measuring vital signs, tumor status, adverse events [ Time Frame: At Months 6, 12, 18 and 24 ]
4. Parts B & C: TRX518 peak concentration (Cmax) [ Time Frame: At each study visit from baseline up to end of treatment visit ]
   Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518
5. Parts B & C: Time to peak concentration (Tmax) [ Time Frame: At each study visit from baseline up to end of treatment visit ]
   Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518
6. Parts B & C: Area under the curve (AUC) [ Time Frame: At each study visit from baseline up to end of treatment visit ]
   Observations of the distribution, duration of effects and chemical changes of TRX518 in the body and the effects and routes of the body's elimination of TRX518
7. Parts B & C: Evaluate multi-dose TRX18 monotherapy for any evidence of antitumor activity (objective response rate, [ORR] progression free survival [PFS], duration of response and overall survival [OS]; RECIST v1.1 will be utilized [ Time Frame: Every 8 weeks while on study treatment and every 12 weeks for survival until death or lost to follow up. ]
   objective response rate [ORR], progression free survival [PFS], duration of response [DoR] and overall survival [OS]); RECIST v1.1 criteria will be utilized
8. Parts B & C: Evaluate the effect of multi-dose TRX518 monotherapy on lymphoid cell subset number and function [ Time Frame: At baseline and at various timepoints up to end of treatment visit ]
9. Parts B & C: Assess TRX518 immunogenicity [ Time Frame: At baseline and at various timepoints up to end of treatment visit ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria (Parts B & C):

• 18 years or older
• Histologically confirmed unresectable Stage III or Stage IV malignant melanoma, or other solid tumor malignancies
• Failed to respond to or relapsed following standard treatment, declined or was not eligible for standard treatment.
• Expected survival of at least 12 weeks.
• Eastern Cooperative Oncology Group performance status score of 0 or 1 is required.
• Evidence of adequate organ function by standard laboratory tests.

Exclusion Criteria (Parts B & C):

• Evidence of progression of central nervous system (CNS) metastases or symptomatic CNS metastases within 35 days prior to dosing.
• Ocular melanoma which has not metastasized or presence of a non-solid tumor.
• A history of any major surgery within 4 weeks prior to dosing.
• Any history of antitumor therapy completed within 28 days prior to dosing.
• Subjects with active autoimmune disease or history of known or suspected autoimmune disease, with the exception of subjects with isolated vitiligo, resolved childhood asthma/atopy, psoriasis not requiring systemic treatment and controlled thyroid disorders.
• Clinically significant heart disease, defined as NYHA Class III or IV.
• Any significant systemic infection requiring IV antibiotics.
• Known to be human immunodeficiency virus (HIV) positive, have hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCAb) unless HCV RNA undetected/negative.
• Treatment with any other anti-human GITR monoclonal antibody (mAb) or immunomodulatory therapy 42 days prior to dosing (30 days for Interleukin-2 & Interferon-α, 7 days for Topical Imiquimod).
• Adverse events from prior anti-cancer therapy that have not resolved to grade ≤1 except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy.
• Use of any investigational drugs within 30 days prior to dosing.
• Any condition that requires or is likely to require treatment with pharmacologic doses of systemic corticosteroids. Subjects are permitted to receive physiologic replacement of corticosteroid therapy (≤ 10 mg prednisone daily).

Contacts and Locations

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Contacts

Contact: Cyndi Sirard, MD		csirard@leaptx.com
Contact: Reena Lynam		rlynam@leaptx.com

Locations

United States, New York
Immunotherapeutics Core / Memorial Sloan Kettering Cancer Center	Recruiting
New York, New York, United States, 10065
Contact 646-888-4593
Principal Investigator: Jedd Wolchok, MD, PhD

Sponsors and Collaborators

Leap Therapeutics, Inc.

Cancer Research Institute, New York City

Investigators

Principal Investigator:	Principle Investigator: Jedd Wolchok, MD, PhD	Memorial Sloan Kettering Cancer Center

More Information

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Additional Information:

Melanoma Trials at MSKCC 

Responsible Party:	Leap Therapeutics, Inc.
ClinicalTrials.gov Identifier:	NCT01239134 History of Changes
Other Study ID Numbers:	TRX518-001
First Posted:	November 11, 2010
Last Update Posted:	August 14, 2018
Last Verified:	August 2018

Keywords provided by Leap Therapeutics, Inc.:

Malignant melanoma; Metastatic; Unresectable; Stage III or Stage IV; Solid tumor

Additional relevant MeSH terms:

Melanoma; Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors	Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas