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A Phase 1 Dose-Escalation Study to Determine the Safety of TH-302 in Combination With Sunitinib in Patients With Advanced Renal Cell Carcinoma,Gastrointestinal Stromal Tumors and Pancreatic Neuroendocrine Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Advanced Renal Cell Carcinoma, Gastrointestinal Stromal Tumors, Pancreatic Neuroendocrine Tumors

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Trial Information

A Phase 1 Dose-Escalation Study to Determine the Safety of TH-302 in Combination With Sunitinib in Patients With Advanced Renal Cell Carcinoma,Gastrointestinal Stromal Tumors and Pancreatic Neuroendocrine Tumors


This Phase 1 dose-escalation study will use a classic dose escalation design to determine
the MTD of TH-302 when used in combination with sunitinib. The study will be divided into
two parts completed in succession to determine the recommended phase 2 dose (RP2D) for dose
expansion.

Part A:

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 and 2 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.

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 < 1 subject experienced a DLT.
The maximum dose of TH-302 will be 575 mg/m2.

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

TH-302 will be administered by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a
42-day cycle (6 weeks).

The dose of sunitinib will remain fixed: 50 mg administered PO daily on days 1 to 28 day of
a 42-day cycle (6 weeks). On days when both sunitinib and TH-302 are administered,
sunitinib should be administered at least 2 hours before or at least 2 hours after
completion of the TH-302 dose.

Part B:

Once the MTD from Part A has been determined, Part B can commence.

The initial dose of TH-302 will be one dose level higher than the MTD established in Part A.
The dose of TH-302 will be escalated in cohorts of 3-6 subjects. A Dose Level at the MTD
established in Part A will be built into the study in the event that subjects experience
excessive toxicity at the initial dose. 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.

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 < 1 subject experienced a DLT.

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

TH-302 will be administered by IV infusion over 30-60 minutes on Days 8, 15 and 22 of a
42-day cycle (6 weeks).

The dose of sunitinib will remain fixed: 37.5 mg administered PO daily on days 1 to 28 of a
42-day cycle (6 weeks).

On days when both sunitinib and TH-302 are administered, sunitinib should be administered at
least 2 hours before or at least 2 hours after completion of the TH-302 dose.

An additional 10 RCC subjects will be enrolled at the recommended phase 2 dose (RP2D) for
the dose expansion portion of the study.


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

- Pathologically confirmed diagnosis of

- advanced RCC or

- GIST after disease progression on or intolerance to imatinib mesylate (dose
escalation only)

- Unresectable locally advanced or metastatic pancreatic neuroendocrine tumors
(dose escalation only)

- Recovered from reversible toxicities of prior therapy

- Evaluable disease by RECIST criteria (at least one target or non-target lesion for
dose escalation cohorts; at least 1 target lesion for dose expansion cohort)

- ECOG performance status of 0 - 2

- Life expectancy of at least 3 months

- Acceptable liver function:

- Bilirubin less than or equal to 1.5 times upper limit of normal (ULN)

- AST (SGOT) and ALT (SGPT) less than or equal to 3.0 times ULN

- Acceptable renal function:

- Serum creatinine ≤ Upper Limit Normal,

- Acceptable hematologic status (without hematologic support):

- ANC greater than or equal to 1500 cells/μL

- Platelet count greater than or equal to 100,000/μL

- Hemoglobin great than or equal to 9.0 g/dL

- Acceptable cardiac function:

- Normal 12-lead ECG (clinically insignificant abnormalities permitted)

- LVEF normal by MUGA or echocardiogram

- Urinalysis: No clinically significant abnormalities

- Acceptable thyroid function

- All women of childbearing potential must have a negative serum pregnancy test and all
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

Exclusion Criteria:

- Prior therapy with more than 2 myelosuppressive cytotoxic chemotherapy regimens (does
not include neoadjuvant and adjuvant therapy)

- Current use of drugs with known cardiotoxicity or known interactions with sunitinib
(see product label)

- Anticancer treatment with radiation therapy, chemotherapy, targeted therapies
(erlotinib, lapatinib, etc.), immunotherapy, hormones or other antitumor therapies
within 3 weeks prior to study entry (6 weeks for nitrosoureas or mitomycin C)

- Significant cardiac dysfunction:

- Cardiac events within 12 months prior to treatment including MI and
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic
CHF, cerebrovascular accident or transient ischemic attack or pulmonary embolism

- > Grade 2 QTc prolongation

- Requirement for antiarrhythmics

- Uncontrolled arrhythmias within the past 6 months

- Angina pectoris requiring antianginal medication within the past 6 months

- Clinically significant valvular heart disease

- Poorly controlled hypertension despite adequate blood pressure medication

- Seizure disorders requiring anticonvulsant therapy

- Known brain metastases (unless previously treated and well controlled for a period of
greater than or equal to 3 months)

- Other active malignancy, except for adequately treated non-melanoma skin cancer, in
situ cancer

- Severe chronic obstructive or other pulmonary disease with hypoxemia (requires
supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse
oximetry after a 2 minute walk) or in the opinion of the investigator any
physiological state likely to cause normal tissue hypoxia

- 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

- Prior therapy with an hypoxic cytotoxin

- Subjects who participated in an investigational drug or device study within 21 days
prior to study entry

- Known infection with HIV or active infection with hepatitis B or hepatitis C

- Subjects who have exhibited allergic reactions to a structural compound or biological
agent similar to TH-302

- Females who are pregnant or breast-feeding

- 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

- Unwillingness or inability to comply with the study protocol for any reason

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

To determine the MTD and DLT(s) of TH-302 when used in combination with sunitinib.

Outcome Time Frame:

Two years

Safety Issue:

Yes

Principal Investigator

Alexander Starodub, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

IU Health Goshen Center for Cancer Care

Authority:

United States: Food and Drug Administration

Study ID:

TH-CR-410

NCT ID:

NCT01381822

Start Date:

June 2011

Completion Date:

June 2013

Related Keywords:

  • Advanced Renal Cell Carcinoma
  • Gastrointestinal Stromal Tumors
  • Pancreatic Neuroendocrine Tumors
  • TH-302
  • Advanced Renal Cell Carcinoma
  • RCC
  • Gastrointestinal Stromal Tumors
  • GIST
  • Phase 1
  • Sunitinib
  • Pancreatic Neuroendocrine Tumors
  • PNET
  • Carcinoma
  • Carcinoma, Renal Cell
  • Neuroendocrine Tumors
  • Gastrointestinal Stromal Tumors
  • Adenoma, Islet Cell

Name

Location

University of IowaIowa City, Iowa  52242
IU Simon Cancer CenterIndianapolis, Indiana  46202
IU Health Goshen Center for Cancer CareGoshen, Indiana  46526