A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01864538
Recruitment Status : Terminated (Lack of enrollment)
First Posted : May 29, 2013
Results First Posted : August 16, 2017
Last Update Posted : September 25, 2017
Information provided by (Responsible Party):
Threshold Pharmaceuticals

May 13, 2013
May 29, 2013
July 14, 2017
August 16, 2017
September 25, 2017
May 2013
September 2015   (Final data collection date for primary outcome measure)
Overall Survival [ Time Frame: 1 year ]
Overall Survival [ Time Frame: 2 years ]
Complete list of historical versions of study NCT01864538 on Archive Site
Not Provided
  • Identify Potential Imaging, Serum, and Tissue Biomarker(s) That Predict for Response and Toxicities to TH-302. [ Time Frame: 2 years ]
  • Incidence and Severity of Adverse Events Associated With TH-302. [ Time Frame: 2 years ]
Not Provided
  • Correlation of Efficacy Endpoints Including the Changes in RECIST Measurements With Established and Potential Biomarkers and Changes in Biomarkers [ Time Frame: 2 Years ]
  • The Correlation of Toxicity (CTCAE 4.03) With Biomarkers and Changes in Biomarkers [ Time Frame: 2 years ]
  • Correlation of TH-302 Administration With Tumor Immune Infiltrates [ Time Frame: 2 years ]
  • Correlation of Characteristics of Melanoma Such as BRAF Status With HIF Activity or Hypoxic Biomarkers Thereof, and Activity of TH-302 [ Time Frame: 2 years ]
A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma
A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma
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.
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.
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Metastatic Melanoma
Drug: TH-302
480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
Experimental: TH-302
480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
Intervention: Drug: TH-302
Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
September 2015
September 2015   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  1. At least 18 years of age
  2. 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)
  3. Histologically documented cutaneous or mucosal malignant melanoma, which is recurrent or metastatic and is not curable by surgical or other means.
  4. 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.
  5. Ability and availability to complete all prescribed biomarker studies (Screening and after Cycle 2).
  6. Recovered to Grade 1 from reversible toxicities of prior therapy
  7. 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)
  8. ECOG performance status of 0 - 1.
  9. 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
  10. Acceptable liver function
  11. Acceptable renal function
  12. Acceptable hematologic status (without growth factor support for neutropenia or transfusion dependency):
  13. Normal 12-lead ECG (clinically insignificant abnormalities permitted)
  14. 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:

  1. Anticancer treatment with radiation therapy, targeted therapies, chemotherapy, immunotherapy, hormones or other antitumour therapies within 28 days prior to first dose of TH-302.
  2. Subjects who have received any other investigational drug or agent within 28 days of first dose of TH-302
  3. Current use of drugs with known cardiotoxicity
  4. Significant cardiac dysfunction:
  5. Seizure disorders requiring anticonvulsant therapy
  6. 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).
  7. 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
  8. 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.
  9. Major surgery, other than diagnostic surgery, within 4 weeks prior to Cycle 1 Day 1, without complete recovery
  10. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
  11. Prior therapy with an hypoxic cytotoxin
  12. Known infection with HIV or active infection with hepatitis B or hepatitis C
  13. History of allergic reaction to a structural compound or biological agent similar to TH-302
  14. Pregnancy or breast-feeding
  15. 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
  16. Unwillingness or inability to comply with the study protocol for any reason.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
Contact information is only displayed when the study is recruiting subjects
Canada,   United States
Not Provided
Not Provided
Threshold Pharmaceuticals
Threshold Pharmaceuticals
Not Provided
Study Director: Tillman Pearce, MD Threshold Pharmaceuticals
Threshold Pharmaceuticals
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP