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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 in Subjects With Relapsed/Refractory Multiple Myeloma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Multiple Myeloma

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Trial Information

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 in Subjects With Relapsed/Refractory Multiple Myeloma


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 as a monotherapy with a Simon two-stage expansion at the MTD. The study
will also investigate the DLTs, MTD, safety and preliminary efficacy of TH-302 in
combination with Bortezomib. As such, the study is separated into three parts. Treatment
will be administered on a 21-day cycle, until disease progression or unacceptable toxicity,
or 12 cycles have been completed.

Part A: Monotherapy TH-302 Dose Escalation

The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302
will be 240 mg/m2. A Dose Level minus 1 will be built into the study in the event that
subjects experience excessive toxicity at Dose Level 1. Dose escalation will continue with
approximately 40% increases from the previous dose level; however lower dose increases of
20-39% may be implemented after consultation between the Investigators, Medical Monitor and
Sponsor with the percent increase dependent on the current dose level and the cumulative
safety data.

Before applying the dose escalation rules, all three subjects in a given cohort dose level
must complete 21 days (1 cycle) of therapy and safety evaluation. If the first 3 subjects
within a cohort tolerate the first 21 days of therapy without dose limiting toxicity (DLT)
as defined below, the next cohort may proceed.

If one of 3 subjects experiences a DLT during the first treatment cycle, 3 additional
subjects will be enrolled at that dose level for a total of 6 subjects in that cohort. If
no additional DLTs are observed, the next dose escalation will resume. However, if 2 or
more of 6 subjects within a cohort experience a DLT, that dose will be considered to exceed
the MTD. If at any time during a cohort, >2 subjects experience a drug-related DLT, the MTD
will have been exceeded, additional enrollment will cease and dose escalation will stop.

The MTD will then be defined at the highest dose level whereby 6 subjects were treated and
no more than 1 subject experienced a DLT and at least 2 subjects had a DLT at the next
higher dose level. The maximum safe dose of TH-302 will be the single agent MTD or the
highest dose tested in that study if the MTD was not reached.

Once the MTD has been reached an additional 3 subjects (for a total of 9) will be dosed at
the MTD to access efficacy. If 2 DLTs do not occur in any dose level of the dose escalation
of Part A and the highest dose tested is defined as the MTD, an additional 3 subjects (for a
total of 9) will be dosed at the highest dose tested.

A Simon two-stage design will be implemented at the MTD. If there is sufficient activity (1
or more subjects of the first 9 subjects achieves partial response or better), then
monotherapy enrollment will be expanded to Part B. If there is insufficient activity (no
partial response or better in 9 subjects), then no further investigation of TH-302 as a
monotherapy is warranted and investigation of TH-302 in combination with bortezomib begins
in Part C.

Part B: Monotherapy TH-302 MTD Dose Expansion

If there is sufficient activity in Part A at the MTD (at least 1 of 9 subjects achieves
partial response or better), an additional 15 subjects will be enrolled for a total of 24
subjects treated at the MTD. After the last patient in the Part B expansion has completed
Cycle 1 and review of the cumulative safety data confirms that the monotherapy is
well-tolerated, patients may be enrolled into Part C of the trial (TH-302 in combination
with bortezomib).

Part C: TH-302 Dose Escalation in combination with bortezomib

The dose of TH-302 will be escalated in cohorts of 3-6 subjects. The initial dose of TH-302
will be 240 mg/m2. Follow same DLTs as above. A Dose Level minus 1 will be built into the
study in the event that subjects experience excessive toxicity at Dose Level 1. Dose
escalation will continue with 40% increases from the previous dose level; however lower dose
increases of 20-39% may be implemented after consultation between the Investigators, Medical
Monitor and Sponsor with the percent increase dependent on the current dose level and the
cumulative safety data.

The dose of bortezomib will remain fixed at 1.3 mg/m2. If a subject experiences a DLT, 3
additional subjects will be enrolled at that dose level for a total of 6 subjects in that
cohort. If no additional DLTs are observed, dose escalation will resume. However, if 2 or
more of 6 subjects within a cohort experience a DLT, that dose will be considered to exceed
the MTD. The MTD will then be defined at the next lower dose level whereby 6 subjects were
treated and no more than one subject experienced a DLT. The maximum safe dose of TH-302 and
1.3 mg/m2 of bortezomib will be the combination MTD or the highest dose tested if the MTD
was not reached.

The MTD will be based on toxicities occurring during the first cycle.

An additional 6 subjects (for a total of 12) will be enrolled at the MTD for the dose
expansion portion of the study. If 2 DLTs do not occur in the dose escalation of Part C and
the highest dose tested is defined as the MTD, an additional 6 subjects (for a total of 12)
will be dosed at the highest dose tested.

TH-302 will be administered by IV infusion over 30-60 minutes on Days 1, 4, 8 and 11 of a 21
day cycle.

Bortezomib will be administered by IV push over 3-5 seconds on Days 1, 4, 8 and 11 of a 21
day cycle. On days where bortezomib and TH-302 are given on the same day, administer
bortezomib at least 2 hours after TH-302 infusion.

There will be no dose escalation in individual subjects. Missed doses will not be made up.
Doses of TH 302 or bortezomib may be rescheduled for +2 days, if the scheduled dose falls on
a holiday. Anticipated delays of >2 days should be discussed with the medical monitor.

Subjects who successfully complete a 3-week treatment cycle without evidence of significant
treatment-related toxicity or progressive disease will continue to receive treatment for up
to 12 cycles.

Up to six subjects may be enrolled in any of the other cohorts below the MTD. Subjects
receiving less than 4 days of dosing and not experiencing a DLT during Cycle 1 will be
replaced. In addition, subjects not completing the first 21 days of Cycle 1 and not
experiencing a DLT may be replaced at the discretion of the Principal Investigator.


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.

- Subjects with refractory disease are allowed to participate on study. (Refractory
disease is defined as progressive disease within 60 days of last therapy or
progression while on therapy).

- Receipt of at least two prior therapies (induction therapy with stem cell transplant
with or without maintenance is considered a prior therapy) including prior therapy
with a bortezomib-containing regimen (and did not discontinue due to toxicity) and a
lenalidomide- or thalidomide-containing regimen

- Subjects with measurable disease defined as at least one of the following:

- Serum M-protein ≥ 0.5 mg/dl

- Urine M-protein ≥ 200 mg/24 h

- Serum FLC assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l)

- Measurable plasmacytoma (should be measured by CT or PET/CT within 28 days of
initial investigational agent dosing).

- ECOG performance status of less than or equal to 2 (see Appendix B)

- Acceptable liver function:

- Total bilirubin ≤ 1.5 times upper limit of normal (x ULN). If total bilirubin is
elevated, check direct and if normal then the subject is eligible

- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3.0 x ULN (≤ 5.0
x ULN if due to myeloma involvement).

- Alkaline phosphatase ≤ 3.0 x ULN (≤ 5.0 x ULN if due to leukemic involvement)

- Acceptable renal function:

- Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance above 40 mL/min using
the formula of Cockcroft and Gault, or a 24 hr creatinine clearance if borderline

- Acceptable hematologic status (without hematologic support):

- ANC ≥ 1000 cells/μL (growth factors may not be used within 7 days prior to
evaluation)

- Platelet count ≥ 75,000/μL (for subjects in whom < 50% of bone marrow nucleated cells
are plasma cells); platelet count > 50,000/μL for subjects in whom ≥ 50% of bone
marrow nucleated cells are plasma cells (without transfusion during the previous 14
days prior to evaluation)

- Hemoglobin ≥ 8.0 g/dL (without transfusion during the previous 14 days prior to
evaluation).

- All women of childbearing potential must have a negative serum pregnancy test and
women and men subjects must agree to use effective means of contraception (surgical
sterilization or the use or barrier contraception with either a condom or diaphragm
in conjunction with spermicidal gel or an IUD) with their partner from entry into the
study through 6 months after the last dose

- 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 with non secretory or hyposecretory MM

- POEMS syndrome (polyneuropathy, organomegaly, endrocintopathy, monoclonal gammothy
and skin changes.

- Plasma cell leukemia

- Waldnestrom's macroglobinemia

- Subject with known or suspected amyloidosis

- Corticosteroid therapy in a dose equivalent to dexamethasone > 1.5 mg/day or
prednisone > 10 mg/day within 2 weeks prior to first dose, Subjects may be receiving
chronic corticosteroids if they are being given for disorders other than multiple
myeloma if they meet the above

- Planned radiation therapy that occurs after the start of therapy

- Localized radiation therapy to only measurable disease site(s) within 4 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 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

- All previous cytotoxic therapies for multiple myeloma must have been completed at
least 3 weeks prior to start of study. Biologic, novel therapy or corticosteroids
must have been completed at least 2 weeks prior to start of study.

- 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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

safety and tolerability of TH-302 monotherapy and in combination with bortezomib in subjects with relapsed/refractory multiple myeloma

Outcome Time Frame:

2 years

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

TH-CR-408

NCT ID:

NCT01522872

Start Date:

February 2012

Completion Date:

January 2014

Related Keywords:

  • Multiple Myeloma
  • TH-302
  • Relapsed/Refractory Multiple Myeloma
  • Bortezomib
  • Phase 1/2
  • Hypoxia
  • Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

Dana-Farber Cancer InstituteBoston, Massachusetts  02115
Massachusetts General HospitalBoston, Massachusetts  02114-2617
Moffitt Cancer CenterTampa, Florida  33612
Colorado Blood Cancer InstituteDenver, Colorado  80218