Open-label Study of TH-302 and Dexamethasone With or Without Bortezomib or Pomalidomide in Subjects With Relapsed/Refractory Multiple Myeloma

Sponsor

Threshold Pharmaceuticals (Industry)

Overall Status

Unknown status

CT.gov ID

NCT01522872

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

9.8

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase 2 study is designed to evaluate the safety and tolerability activity of TH-302 and dexamethasone with or without bortezomib or pomalidomide in subjects with relapsed/refractory multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: TH-302 Drug: TH-302 and Dexamethasone Drug: TH-302 Dose Escalation and Dexamethasone in Combination with Bortezomib Drug: TH-302 Dose Escalation and Dexamethasone in Combination with Pomalidomide	Phase 1/Phase 2

Detailed Description

This is the initial study of TH-302 in subjects with relapsed/refractory multiple myeloma. It is an open-label dose-escalation study to determine the DLTs, MTD, safety and preliminary efficacy of TH-302 and dexamethasone with a Simon two-stage expansion at the MTD. The study will also investigate the DLTs, MTD, safety and preliminary efficacy of TH-302, dexamethasone and bortezomib; and the DLTs, MTD, safety and preliminary efficacy of TH-302, dexamethasone and pomalidomide. As such, the study is separated into four parts. Treatment will be administered until disease progression or unacceptable toxicity, or 12 cycles (Arm A, Arm B and Arm C) or 9 cycles (Arm D) have been completed.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

98 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Open-label Study to Assess the Safety, Tolerability and Preliminary Efficacy of TH-302, A Hypoxia-Activated Prodrug, and Dexamethasone With or Without Bortezomib or Pomalidomide in Subjects With Relapsed/Refractory Multiple Myeloma

Study Start Date :

Feb 1, 2012

Anticipated Primary Completion Date :

Sep 1, 2016

Anticipated Study Completion Date :

Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Monotherapy TH-302 Dose Escalation	Drug: TH-302
Experimental: TH-302 and Dexamethasone Dose Expansion	Drug: TH-302 and Dexamethasone
Experimental: TH-302 Dose Escalation and Dexamethasone with Bortezomib	Drug: TH-302 Dose Escalation and Dexamethasone in Combination with Bortezomib
Experimental: TH-302 Dose Escalation and Dexamethasone with Pomalidomide	Drug: TH-302 Dose Escalation and Dexamethasone in Combination with Pomalidomide

Outcome Measures

Primary Outcome Measures

Number of participants with adverse events (AEs) [Up to 30 days after last dose]
Type of adverse events(AEs) [Up to 30 days after last dose]
Severity of adverse events(AEs) [Up to 30 days after last dose]
dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of TH-302 and dexamethasone with or without bortezomib or pomalidomide [2 years]
recommended Phase 2 dose for TH-302 and dexamethasone with or without bortezomib or pomalidomide [2 years]

Secondary Outcome Measures

Overall Survival (OS) [Up to 12 weeks post treatment]
Progression-free survival(PFS) [Up to 12 weeks post treatment]
Duration of Response (DOR) [Up to 12 weeks post treatment]
relationship between hypoxia within the bone marrow of subjects with relapsed/refractory multiple myeloma and response to TH-302 and dexamethasone with or without bortezomib or pomalidomide using markers of hypoxia [Up to 12 weeks post treatment]
Maximum plasma concentration of TH-302 and bortezomib [Cycle 1 Day 1 predose and up to 24 hours postdose]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 IRB/Ethics Committee.
Relapsed/refractory multiple myeloma for which no standard therapy options are anticipated to result in a durable remission.
Receipt of at least two prior therapies as indicated by protocol
Subjects with measurable disease
ECOG performance status of less than or equal to 2
Acceptable liver function
Acceptable renal function
Acceptable hematologic status
For Part A, B, C subjects: Women of childbearing potential must have a negative serum pregnancy test and women and men subjects must agree to use effective means of contraception with their partner as indicated by protocol For Part D subjects: a negative serum pregnancy test is required within 10- 14 days prior to initiating with pomalidomide, AND a negative serum pregnancy test within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control at least 28 days before she starts taking pomalidomide.

Women of childbearing potential must enroll into and follow all requirements of the POMALYST REMS program, which includes adhering to the scheduled pregnancy testing.

Men must agree to use a latex or synthetic condom during sexual contact with women of child bearing potential even if they have had a vasectomy.

All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure, or when a female patient misses her period or if there is any abnormality in her menstrual bleeding.

Subjects must adhere to the study visit schedule and other protocol requirements and receive outpatient therapy and laboratory monitoring at the institute that administers the study drug.

Exclusion Criteria

Subjects who meet any of the following exclusion criteria are not eligible to be enrolled in this study:

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes.)
Waldenstrom's macroglobulinemia
Localized radiation therapy to only measurable disease site(s) within 2 weeks of treatment
New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within 6 months prior to Day 1, or unstable arrhythmia
Significant neuropathy (Grade 3 or 4, or Grade 2 with pain) at the time of enrollment or within 14 days before enrollment
Symptomatic brain metastases (unless previously treated and well controlled for a period of ≥ 3 months)
Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy within 14 days prior to the first dose
Previously treated malignancies, except for adequately treated non-melanoma skin cancer (basal cell or squamous cell), in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years
Subjects who participated in an investigational drug or device study within 2 weeks prior to study entry
Known or suspected active infection with HIV, hepatitis A, hepatitis B, or hepatitis C
Subjects who have exhibited allergic reactions to a similar structural compound, biological agent, or formulation similar to TH-302, bortezomib (for subjects enrolled in Part C only), pomalidomide (Part D), dexamethasone or pimonidazole
Females who are pregnant or breast-feeding
Concomitant psychiatric disease or medical 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
Previous cytotoxic therapies for multiple myeloma within 3 weeks prior to study entry (2 weeks for biologic, novel therapy or corticosteroids)
Subjects who have been on hormone replacement less than 2 months (subjects on hormone replacement for at least 2 months will not be excluded provided the HRT regimen remains unchanged during the conduct of the study).
Prior peripheral stem cell transplant within 12 weeks of the start of study
Epilepsy or other convulsive disorder requiring active management
Prior therapy with a pomalidomide-containing regimen
Subjects on strong inducers or strong inhibitors of cytochrome P450 CYP3A4 or CYP1A2
Any other medical condition that in opinion of investigator would place patient at increased risk for toxicity during pomalidomide treatment (i.e. history of recurrent or serious thromboembolic events)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pacific Cancer Care	Monterey	California	United States	93940
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Maine Center for Cancer Medicine	Scarborough	Maine	United States	04074
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
6	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	The West Clinic	Southaven	Mississippi	United States	38671
8	New York Oncology Hematology	Albany	New York	United States	12208
9	New York Oncology Hematology	Hudson	New York	United States	12534
10	The West Clinic	Memphis	Tennessee	United States	38120