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

• Sponsor: Threshold Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01864538
• Collaborator: (none)
• Enrollment: 11
• Locations: 7
• Arm: 1
• Actual Duration (Months): 28
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Drug: TH-302	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Biomarker - Enriched Study of TH-302 in Subjects With Advanced Melanoma
• Actual Study Start Date: May 1, 2013
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TH-302 480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.	Drug: TH-302; 480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.

Outcome Measures

Primary Outcome Measures

1. Overall Survival [1 year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic and Research Institute	Los Angeles	California	United States	90025
2	UCLA	Los Angeles	California	United States	90404
3	Columbia University Medical Center	New York	New York	United States	10032
4	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G1Z2
5	Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V5C2
6	London Health Sciences Centre	London	Ontario	Canada	N6A4L6
7	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G2M9

Sponsors and Collaborators

• Threshold Pharmaceuticals

Investigators

• Study Director: Tillman Pearce, MD, Threshold Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Threshold Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01864538
• Other Study ID Numbers: TH-CR-413
• First Posted: May 29, 2013
• Last Update Posted: Mar 26, 2021
• Last Verified: Aug 1, 2017

• Keywords provided by Threshold Pharmaceuticals: TH-302; Advanced Melanoma; Metastatic; Biomarker; Mucosal Melanoma; Evofosfamide
• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Arm/Group Title	TH-302
Arm/Group Description	480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle. TH-302: 480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
Period Title: Overall Study
STARTED	11
COMPLETED	0
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	TH-302
Arm/Group Description	480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle. TH-302: 480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
Overall Participants	11
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	8 72.7%
Male	3 27.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 9.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	10 90.9%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
Canada	3 27.3%
United States	8 72.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TH-302
Arm/Group Description	480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle. TH-302: 480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
Measure Participants	11
Count of Participants [Participants]	11 100%

Adverse Events

Arm/Group Title	TH-302
Arm/Group Description	480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle. TH-302: 480 mg/m2 by iv infusion over 30 - 60 min on Days 1, 8, and 15 of a 28-day cycle.
All Cause Mortality
	TH-302
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	TH-302
	Affected / at Risk (%)	# Events
Total	8/11 (72.7%)
Blood and lymphatic system disorders
Anaemia	1/11 (9.1%)	2
Splenic thrombosis	1/11 (9.1%)	1
Gastrointestinal disorders
Abdominal distension	1/11 (9.1%)	1
Constipation	1/11 (9.1%)	1
General disorders
Fatigue	1/11 (9.1%)	1
Infections and infestations
Cellulitis	1/11 (9.1%)	1
Urinary tract infection	1/11 (9.1%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/11 (9.1%)	1
Other (Not Including Serious) Adverse Events
	TH-302
	Affected / at Risk (%)	# Events
Total	11/11 (100%)
Blood and lymphatic system disorders
Anaemia	2/11 (18.2%)	2
Gastrointestinal disorders
Constipation	4/11 (36.4%)	5
Diarrhoea	3/11 (27.3%)	4
Nausea	3/11 (27.3%)	5
Vomiting	2/11 (18.2%)	4
General disorders
Chills	2/11 (18.2%)	3
Fatigue	6/11 (54.5%)	10
Oedema peripheral	4/11 (36.4%)	4
Pyrexia	3/11 (27.3%)	3
Infections and infestations
Upper respiratory tract infection	3/11 (27.3%)	3
Investigations
Alanine aminotransferase increased	2/11 (18.2%)	2
Aspartate aminotransferase increased	2/11 (18.2%)	2
Blood alkaline phosphatase increased	2/11 (18.2%)	2
Weight decreased	3/11 (27.3%)	3
Metabolism and nutrition disorders
Decreased appetite	6/11 (54.5%)	7
Dehydration	2/11 (18.2%)	2
Musculoskeletal and connective tissue disorders
Muscular weakness	2/11 (18.2%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	2/11 (18.2%)	2
Nervous system disorders
Dizziness	2/11 (18.2%)	2
Headache	3/11 (27.3%)	3
Renal and urinary disorders
Dysuria	2/11 (18.2%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/11 (27.3%)	4
Skin and subcutaneous tissue disorders
Erythema	2/11 (18.2%)	2
Pruritus	2/11 (18.2%)	3
Rash	3/11 (27.3%)	3
Skin hyperpigmentation	3/11 (27.3%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.