Dose Escalation Study of Pazopanib Plus TH-302 (PATH)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Comprehensive Cancer Network
GlaxoSmithKline
Threshold Pharmaceuticals
Information provided by (Responsible Party):
Herbert Hurwitz, MD, Duke University Medical Center
ClinicalTrials.gov Identifier:
NCT01485042
First received: November 30, 2011
Last updated: April 8, 2014
Last verified: April 2014
  Purpose

3 STUDY RATIONALE Based upon the above rationale, the investigators propose a phase I study combining Pazopanib with TH-302 in advanced solid tumors. Pazopanib is FDA approved at a dose of 800mg per day. Using this dose ensures consistency with standard clinical use. It also ensures using the dose most likely to induce maximal hypoxia, which in turn will help ensure maximal local activation of TH-302 (a hypoxia activated prodrug). TH-302 can be given as monotherapy at a weekly dose of 575 mg/m2. When TH-302 is combined with full doses of various chemotherapeutics, the recommended dose of TH-302 has ranged from 240 to 480 mg/m2. Little overlapping toxicity between TH-302 and pazopanib is expected. However to ensure patient safety, the starting dose for the combination will be conservative and use the TH-302 dose found safe with the majority of cytotoxic agents, 340 mg/m2 given days 1,8, 15 on an every 28 day cycle.

Using a standard 3+3 design, the investigators will add increasing doses of TH-302 (340 mg/m2, 480 mg/m2, 575 mg/m2 given weekly, 3 weeks on/1 week off (the standard TH-302 dosing schedule) to the full monotherapy dose of pazopanib (800 mg p.o daily) with expected accrual ranging from 12-18 subjects. Once the recommended phase II dose is identified, the investigators will then enroll an expanded cohort of approximately 12-18 (i.e. total of 30 subjects overall) patients to better define the tolerability of this study drug combination.

4 STUDY OBJECTIVES 4.1 Primary

  • To define the maximal tolerated dose (if any) and the recommended phase II doses for the combination of pazopanib plus TH-302 in patients with advanced solid tumors 4.2 Secondary
  • To describe any dose limiting and non dose-limiting toxicities of this drug combination

Condition Intervention Phase
Solid Tumors
Drug: Pazopanib and TH-302
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Phase I Dose Escalation of Pazopanib Plus TH-302 in Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Duke University:

Primary Outcome Measures:
  • Maximal tolerated dose [ Time Frame: 12-18 months ] [ Designated as safety issue: Yes ]
    To define the maximal tolerated dose (if any) and the recommended phase II doses for the combination of pazopanib plus TH-302 in patients with advanced solid tumors


Secondary Outcome Measures:
  • Dose limiting or non dose limiting toxicities [ Time Frame: 12-18 months ] [ Designated as safety issue: Yes ]
    To describe any dose limiting and non dose-limiting toxicities of this drug combination


Estimated Enrollment: 50
Study Start Date: December 2011
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose Escalation
This is a Phase 1 dose escalation with an expanded cohort that will enroll at MTD.
Drug: Pazopanib and TH-302
Pazopanib 800 mg daily TH-302 IV on Days 1, 8, 15 at MTD Subjects will receive this regimen until disease progression.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically and/or cytologically confirmed malignant solid tumor that is refractory to standard therapies, or for which no standard therapies exist, or for whom pazopanib would be considered a therapeutic option.
  • Disease must be measurable by RECIST 1.1 criteria (see Appendix 1).
  • Age ≥ 18 years
  • Karnofsky Performance status ≥ 80% (see Appendix 2)
  • Life expectancy of at least 3 months
  • Adequate bone marrow function as shown by:

    • ANC ≥ 1.5 x 109
    • Platelets ≥ 100 x 109/L
    • Hemoglobin ≥ 9 g/dL; Erythropoietin and transfusion support is permitted provided treatments are not required more than every 8 weeks. Hemoglobin must be stable above or equal to 9 g/dL for at least 2 weeks prior to day 1of study drug without blood transfusion to maintain hemoglobin level.
  • Adequate liver function as shown by:

    • serum bilirubin ≤ 1.5x ULN
    • PT/PTT/INR ≤ 1.5x ULN
    • ALT and AST ≤ 2.5x ULN
  • Adequate renal function: creatinine clearance (estimated) ≥ 50 cc/min by Cockroft-Gault or 24 hour urine (see Appendix 6).
  • Baseline MUGA or ECHO must demonstrate LVEF ≥ 50%
  • TSH, T3 and T4 within normal limits; Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism.
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days from day 1 of study drug; both men and women must be willing to use two methods of contraception, one of them being a barrier method during the study and for 6 months after last study drug administration.
  • Signed informed consent

Exclusion Criteria:

  • Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks from day 1 of study drug (including investigational agents, chemotherapy, radiation therapy, antibody based therapy, etc.)
  • Patients who:

    • have had a major surgery or significant traumatic injury within 4 weeks from day 1 of study drug,
    • have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or
    • are anticipated to require major surgery during the course of the study.
  • Patients who have exhibited hypersensitivity reactions to pazopanib and/or a structural compound, biological agent, or formulation.
  • Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent with the following exceptions:
  • Intermittent steroids (not to exceed 4 mg every day) may be used on an as-needed basis
  • Patients on physiologic replacement doses of steroids due to adrenal insufficiency for any reason may remain on these medications.
  • Topical, inhaled or intra-articular corticosteroids
  • Active brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases. Treated, asymptomatic metastases are permitted provided the patient has been off steroids for at least 1 month prior to day 1 of study drug.
  • Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or O2 saturation <90% by pulse oximetry after a 2 minute walk or in the opinion of the investigator any physiological state likely to cause systemic or regional hypoxemia.
  • Presence of poorly controlled atrial fibrillation (ventricular heart rate >100 bpm)
  • Previous history of CVA, TIA, angina pectoris, acute MI or history of recent re-perfusion procedures (e.g. PTCA), pulmonary embolus or untreated deep vein thrombosis (DVT) within 6 months from day 1 of study drug.

NOTE: Subjects with recent DVT who have been therapeutically anti-coagulated for at least 6 weeks are eligible.

  • Congestive heart failure (New York Heart Association (NYHA classification, see Appendix 4 functional classification III-IV).
  • Proteinuria at screening demonstrated by urine analysis (UA) > 1+ or 24 hour urine protein ≥ 1 gram/24 hours.
  • Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study as so judged by the treating physician. Examples include but are not limited to:

    • Severely impaired lung function (e.g. use of home O2, history of Idiopathic Lung Disease (ILD), any evidence of ILD on scan.
    • Active or uncontrolled severe infections requiring treatment with antibiotics.
    • Liver disease
    • Poorly controlled hypertension [defined as systolic blood pressure (SBP of >140 mmHg or diastolic blood pressure (DBP) of >90 mmHg] NOTE: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement.
    • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of oral medications (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
  • Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1 of study drug
  • History of hemoptysis within 1 month prior to day 1 of study drug.
  • History of abdominal fistula or gastrointestinal perforation at any point within 6 months prior to day 1 of study drug, unless surgically repaired.
  • Active peptic ulcer disease inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation or gastrointestinal bleeding.
  • Use or need for full dose anticoagulation other than low molecular weight heparin (e.g. Lovenox and no other bleeding risk).
  • Invasion or encasement of a major artery. Abutment without invasion or encasement is permitted.
  • Serious, non-healing wound, active ulcer, or untreated bone fracture as judged by treating physician.
  • Active, bleeding diathesis.
  • Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.
  • Known history of HIV or Hepatitis B or C seropositivity.
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Two acceptable forms of contraceptives must be continued throughout the trial by either sex. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to day 1 of study drug).
  • Concomitant use of CYP3A4 inducers, strong inhibitors or substrates with a narrow therapeutic window.
  • Corrected QTc interval > 480 msec. If QTc interval is > 480 msec, then 2 additional ECGs should be obtained over a brief period of time (e.g., within 15-20 minutes) to confirm the abnormality.
  • Patients unwilling to or unable to comply with the protocol.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01485042

Locations
United States, North Carolina
Duke Cancer Institute
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Herbert Hurwitz, MD
National Comprehensive Cancer Network
GlaxoSmithKline
Threshold Pharmaceuticals
Investigators
Principal Investigator: Herbert I Hurwitz, MD Duke University
  More Information

No publications provided

Responsible Party: Herbert Hurwitz, MD, Associate Professor of Medicine, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT01485042     History of Changes
Other Study ID Numbers: Pro00031123
Study First Received: November 30, 2011
Last Updated: April 8, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:
Phase 1
pazopanib
TH-302
advanced solid tumors

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on April 14, 2014