Immunotherapy Study of Evofosfamide in Combination With Ipilimumab

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Disease Information

Descriptive Information
Brief Title † Immunotherapy Study of Evofosfamide in Combination With Ipilimumab
Official Title † A Phase 1 Immunotherapy Study of Evofosfamide in Combination With Ipilimumab in Patients With Advanced Solid Malignancies
Brief Summary An immunotherapy study combining ipilimumab and evofosfamide for the treatment of patients with confirmed metastatic or locally advanced prostate cancer, metastatic pancreatic cancer, melanoma or human papillomavirus (HPV) negative squamous cell carcinoma of head and neck that have failed to respond to standard therapy, progressed despite standard therapy, for which standard therapy does not offer the potential for increased survival.
Detailed Description Tumor hypoxia can lead to poor effector T cell penetration and immunosuppressive signaling via myeloid-derived suppressor, myofibroblast and regulatory T cells. Disruption of these hypoxic regions within the tumor microenvironment by the hypoxia-directed cytotoxic agent evofosfamide may enhance the ability of the CTLA-4 checkpoint inhibitor ipilimumab to reject otherwise resistant solid tumors. Additionally, induction of immunogenic cell death of tumor cells by evofosfamide may enhance dendritic cell presentation of tumor antigens to lymphocytes in draining lymph nodes, leading to clonal expansion of tumor-specific T cells, especially in combination with ipilimumab.
Study Phase Phase 1
Study Type † Interventional
Study Design †
Primary Outcome Measure † Recommended phase 2 dose (RP2D) determined after maximally tolerated dose is set and four dose expansion cohorts have evaluable data
Secondary Outcome Measure † Maximum tolerated dose (MTD) of this therapy based on number of dose limiting toxicities that occur during the dose escalation phase
Condition † Pancreatic Cancer Melanoma Squamous Cell Carcinoma of the Head and Neck Prostate Cancer
Intervention † DrugEvofosfamide
Study Arms / Comparison Groups Evofosfamide plus Ipilimumab Ipilimumab to be administered at same dose. Evofosfamide dose to be determined during duration of trial
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Drug
Estimated Enrollment † 69
Start Date † May 10, 2017
Completion Date April 2019
Primary Completion Date January 2019
Eligibility Criteria † Inclusion Criteria: 1. Patients must be willing and able to review, understand, and provide written consent before study enrollment 2. Patients must have either a histologically-confirmed metastatic or locally advanced prostate cancer, metastatic pancreatic cancer, melanoma or human papillomavirus (HPV) negative squamous cell carcinoma of head and neck. 3. At least 18 years of age. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky > 60 %) 5. Measurable disease as defined by irRECIST. Patients with castrate-resistant prostate cancer can have measurable or evaluable disease. Patients with evaluable disease must have documented evidence of progressive disease as defined by any of the following: 1. Prostate-specific antigen (PSA) progression: minimum of 2 rising values (3 measurements) obtained a minimum of 7 days apart with the last result being at least >/= 1.0 ng/mL; 2. New or increasing non-bone disease (RECIST 1.1 criteria); 3. Positive bone scan with 2 or more new lesions (PCWG3) 6. Adequate bone marrow function within 7 days and defined as: 1. White Blood Cell (WBC) ≥ 2500 cells/mm3 2. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3cells 3. Absolute lymphocyte count (ALC) >1000 cells/mm3 4. Hemoglobin ≥ 9 g/dL 5. Platelets (PLT) ≥ 75,000 cells/mm3 7. Acceptable renal function within 7 days defined as serum creatinine ≤ 2.0 times the institutional upper limit of normal (ULN) or calculated creatinine clearance ≥ 50 mL/min (by the Cockcroft Gault formula). 8. Acceptable liver function within 7 days of day 1 of therapy defined as: 1. • Bilirubin ≤ 1.5 times institutional ULN; does not apply to patients diagnosed with Gilbert's syndrome. 2. • AST (SGOT) and ALT (SGPT) ≤ 3 times institutional ULN; if liver metastases are present, then ≤ 5 times ULN is allowed. 9. QTc interval of ≤ 450 msec (males) or 470 msec (females) calculated according to Fridericia's formula (QTc = QT/RR0.33; RR=RR interval) 10. Ability and availability to complete all prescribed biopsies (prior to the first evofosfamide dose and between day 15 of Cycle 2 and day 8 of Cycle 3) 11. At least 3 weeks from previous cytotoxic chemotherapy or radiation therapy and at least 5 half-lives or 6 weeks, whichever is shorter, after targeted or biologic therapy excepting prior treatment with CTLA 4, PD-1, or PD-L1 blocking antibodies for which only a 2 week interval is required. Patients with prostate cancer, unless orchiectomy has been performed in them, may continue to receive androgen deprivation therapy (ADT), anti-androgen therapy or therapy that interferes with androgenic stimulation. 12. Patients must have recovered from toxicity related to prior therapy to at least grade 1 (defined by CTCAE 4.0) or baseline level. Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis by the Principal Investigator. 13. Female patients of childbearing age must have a negative serum HCG test within 7 days of study enrollment, unless prior hysterectomy or menopause (defined as age ≥ 55 years and twelve consecutive months without menstrual activity). Female patients should not become pregnant or breast-feed while on this study. 14. Sexually active male and female patients should use effective birth control (abstinence; hormonal or barrier method) for the duration of the study and at least 2 months from last dose. Exclusion Criteria: 1. Active/uncontrolled autoimmune disease: patients with a history of inflammatory bowel disease (including Crohn's disease and ulcerative colitis) and autoimmune disorders such as rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus or autoimmune vasculitis [e.g., Wegener's Granulomatosis] are excluded from this study. 2. Patients with history of any Grade 3 or Grade 4 adverse events from prior ipilimumab therapy, if administered in the past. 3. Patients with history of mild autoimmune disorders - including but not limited to - mild psoriasis or Hashimoto's hypothyroidism, may be included at the discretion of the principle investigator. 4. History of acute diverticulitis, intra-abdominal abscess, GI obstruction, abdominal carcinomatosis or other known risk factors for bowel perforation. 5. Patients on long term systemic steroids (>10 mg daily prednisone equivalent). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll at the discretion of the principle investigator. Inhaled or topical steroids are permitted in the absence of active autoimmune disease. 6. Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs: e.g. a condition associated with frequent diarrhea or chronic skin conditions, recent surgery or colonic biopsy from which the patient has not recovered, or partial endocrine organ deficiencies. 7. Receiving QT-prolonging drugs with a risk of causing torsades de pointes (See Appendix E), unless ECG meets inclusion criteria on a stable dose of the drug and with discussion and agreement with the project clinician 8. History of risk factors for TdP, including family history of long QT syndrome. 9. Sustained systolic blood pressure (BP) >140 mm Hg or 100 mm Hg or
Gender All
Ages 18 Years - N/A
Accepts Healthy Volunteers No
Contacts †† Kristen L. Quigley, 650-455-9622,
Location Countries † United States
Administrative Information
NCT ID † NCT03098160
Organization ID TH-CR-417
Secondary IDs ††
Responsible Party Sponsor
Study Sponsor † Threshold Pharmaceuticals
Collaborators †† M.D. Anderson Cancer Center
Investigators † Principal Investigator: David Hong, MD, M.D. Anderson Cancer Center
Information Provided By
Verification Date March 2017
First Received Date † March 22, 2017
Last Updated Date June 12, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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