- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01864538
A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma
March 24, 2021 updated by: Threshold Pharmaceuticals
The primary objective of this study is to determine the response rate, duration of response,progression-free survival and overall survival of subjects with advanced melanoma treated with TH-302.
Study Overview
Detailed Description
Hypoxia is an independent marker of a poor prognosis for subjects with metastatic melanoma (Simonetti 2012, Lartigau 1997).
Hypoxic melanoma cells are more likely to exhibit a stem-cell like phenotype with an associated increased propensity for invasion, angiogenesis, and metastasis formation compared to normoxic cells.
Moreover, this phenotype is also associated with treatment resistance.
TH-302, a hypoxia activated prodrug (HAP), was designed to target the hypoxic nature of tumours while having a minimal effect on normoxic tissue.
TH-302 belongs to a class of alkylating agents that have significant experimental and clinical activity (Brock 1989).
Preclinical data support the hypothesis that TH-302 targets hypoxic regions of tumours and is also able to kill tumour cells in normoxic regions as a result of cytotoxin diffusion, leading to significant effects on tumour growth (Meng 2011).
TH-302 has been investigated in over 700 subjects with solid tumours or hematologic malignancies, including subjects with metastatic melanoma.
In this subset a disease control rate of 63% (3 subjects with partial responses and 9 subjects with stable disease out of a total of 19) was observed in an early phase clinical trial of TH-302 (Weber 2010).
Predictive biomarkers for response and toxicity have yet to be identified for subjects with advanced melanoma treated with TH-302.
Optimal patient selection may be critical to maximize the clinical benefit.
A predictive biomarker approach will be investigated to try to identify subjects most likely to benefit from TH-302.
Given the hypoxia-targeting mechanism of TH- 302, it is believed that hypoxia biomarkers will be the most informative for identifying subjects likely to benefit from TH- 302; however, additional biomarkers including DNA repair biomarkers will also be investigated.
In addition, this approach will also have potential to synergise with future immunotherapeutic approaches as suppressive T regulatory cells are thought to reside within hypoxic niches within the tumour microenvironment that would be amenable to targeting by TH-302.
Study Type
Interventional
Enrollment (Actual)
11
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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Alberta
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Edmonton, Alberta, Canada, T6G1Z2
- Cross Cancer Institute
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Ontario
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Hamilton, Ontario, Canada, L8V5C2
- Juravinski Cancer Centre
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London, Ontario, Canada, N6A4L6
- London Health Sciences Centre
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Toronto, Ontario, Canada, M5G2M9
- Princess Margaret Hospital
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California
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Los Angeles, California, United States, 90025
- The Angeles Clinic and Research Institute
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Los Angeles, California, United States, 90404
- UCLA
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New York
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New York, New York, United States, 10032
- Columbia University Medical Center
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- At least 18 years of age
- Ability to understand the purposes and risks of the study and has signed a written informed consent form approved by the investigator's Regional Ethics Board/Independent Ethics Committee (REB/IEC)
- Histologically documented cutaneous or mucosal malignant melanoma, which is recurrent or metastatic and is not curable by surgical or other means.
- Adequate tumour tissue (greater than 0.5cm3 preferred, 3 X core biopsy acceptable) available and agreement from subjects that this tissue from their primary and/or metastatic tumour be made available for assessment of potential biomarkers.
- Ability and availability to complete all prescribed biomarker studies (Screening and after Cycle 2).
- Recovered to Grade 1 from reversible toxicities of prior therapy
- Presence of clinically and/or radiologically documented disease. At least one site of disease (which will not be removed during the course of the study) must be uni-dimensionally measurable as per RECIST 1.1 or clinically quantifiable (such as in the case of skin disease)
- ECOG performance status of 0 - 1.
- Prior treatment with any number of immunotherapies (e.g., IL2, ipilimumab), targeted therapies (e.g., vemurafenib) are permitted but no more than one 1 prior chemotherapy
- Acceptable liver function
- Acceptable renal function
- Acceptable hematologic status (without growth factor support for neutropenia or transfusion dependency):
- Normal 12-lead ECG (clinically insignificant abnormalities permitted)
- Female subjects of childbearing age must have a negative urine HCG test unless prior hysterectomy or menopause (defined as age above 55 and twelve months without menstrual activity). Female subjects should not become pregnant or breast-feed while on this study. Sexually active male and female subjects should use effective birth control.
Exclusion Criteria:
- Anticancer treatment with radiation therapy, targeted therapies, chemotherapy, immunotherapy, hormones or other antitumour therapies within 28 days prior to first dose of TH-302.
- Subjects who have received any other investigational drug or agent within 28 days of first dose of TH-302
- Current use of drugs with known cardiotoxicity
- Significant cardiac dysfunction:
- Seizure disorders requiring anticonvulsant therapy
- Progressing brain metastases (unless previously treated and stable disease for a period of greater than or equal to 3 months on repeat MRI following definitive treatment).
- History of other malignancies, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for greater than 2 years
- Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation less than 90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause hypoxia of normal tissue.
- Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, without complete recovery
- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
- Prior therapy with an hypoxic cytotoxin
- Known infection with HIV or active infection with hepatitis B or hepatitis C
- History of allergic reaction to a structural compound or biological agent similar to TH-302
- Pregnancy or breast-feeding
- Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
- Unwillingness or inability to comply with the study protocol for any reason.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: TH-302
480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
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480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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Overall Survival
Time Frame: 1 year
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1 year
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Investigators
- Study Director: Tillman Pearce, MD, Threshold Pharmaceuticals
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
May 1, 2013
Primary Completion (Actual)
September 1, 2015
Study Completion (Actual)
September 1, 2015
Study Registration Dates
First Submitted
May 13, 2013
First Submitted That Met QC Criteria
May 24, 2013
First Posted (Estimate)
May 29, 2013
Study Record Updates
Last Update Posted (Actual)
March 26, 2021
Last Update Submitted That Met QC Criteria
March 24, 2021
Last Verified
August 1, 2017
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- TH-CR-413
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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