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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy TH-302 Dose Escalation<br> | Drug: TH-302<br> <br> |
| Experimental: TH-302 and Dexamethasone Dose Expansion<br> | Drug: TH-302 and Dexamethasone<br> <br> |
| Experimental: TH-302 Dose Escalation and Dexamethasone with Bortezomib<br> | Drug: TH-302 Dose Escalation and Dexamethasone in Combination with Bortezomib<br> <br> |
| Experimental: TH-302 Dose Escalation and Dexamethasone with Pomalidomide<br> | Drug: TH-302 Dose Escalation and Dexamethasone in Combination with Pomalidomide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TH-302, Relapsed/Refractory Multiple Myeloma, Bortezomib, Phase 1/2, Hypoxia, Myeloma, Evofosfamide, Pomalidomide, Pimonidazole