Clinical Trials /

Immunotherapy Study of Evofosfamide in Combination With Ipilimumab

NCT03098160

Description:

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.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Melanoma
  • Pancreatic Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: TH-CR-417
  • NCT ID: NCT03098160

Conditions

  • Pancreatic Cancer
  • Melanoma
  • Squamous Cell Carcinoma of the Head and Neck
  • Prostate Cancer

Interventions

DrugSynonymsArms
EvofosfamideEvofosfamide plus Ipilimumab
IpilimumabEvofosfamide plus Ipilimumab

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Evofosfamide plus IpilimumabExperimentalIpilimumab to be administered at same dose. Evofosfamide dose to be determined during duration of trial
  • Evofosfamide
  • Ipilimumab

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 <90 mm Hg, diastolic BP >100 mm
             Hg or <60 mm Hg

         10. Patients with newly diagnosed, uncontrolled and or untreated cancer; related central
             nervous system diseases are excluded.

         11. Uncontrolled intercurrent illness, including, but not limited to, myocardial
             infarction within 6 months, unstable symptomatic ischemic heart disease, active
             uncontrolled infection requiring systemic therapy, or psychiatric illness/social
             situations that would limit compliance with study requirements.

         12. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             of day 1 of therapy.

         13. Current evidence of active and uncontrolled infection, NYHA Class III-IV CHF,
             documented Child's class B and C cirrhosis, active pancreatitis or uncontrolled
             medical disease which in the opinion of the investigator could compromise assessment
             of efficacy.

         14. Known human immunodeficiency virus (HIV)-positive unless on highly active
             antiretroviral therapy (HAART), and/or known Hepatitis B or C on treatment. Drug
             interactions between those agents and these experimental agents are wholly unknown
             (screening not required).

         15. Known hypersensitivity to the components of study drugs, its analogs, or drugs of
             similar chemical or biologic composition.

         16. Any live vaccine or non-oncology vaccine therapy used for prevention of infectious
             diseases (for up to one month prior to or after any dose of ipilimumab).

         17. Concomitant therapy with any of the following: IL-2, interferon or other non-study
             immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; or other
             investigational therapies.

         18. Receiving medications that are strong inhibitors or inducers of CYP3A4 (Appendix D).

         19. Use of any other concurrent investigational agents or anticancer agents including
             hormonal therapy, except in the case of prostate cancer patients who are being treated
             anti-androgen or bone targeting therapies.

         20. Female patients who have been on hormone replacement therapy (HRT) for menopausal
             symptoms for a period of at least 2 months will not be excluded from the study
             provided the HRT regimen remains unchanged during the conduct of the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) determined after maximally tolerated dose is set and four dose expansion cohorts have evaluable data
Time Frame:Approximately 8-12 months
Safety Issue:
Description:Threshold and MD Anderson Cancer Center to evaluate patient safety data to determine proper dose

Secondary Outcome Measures

Measure:Maximum tolerated dose (MTD) of this therapy based on number of dose limiting toxicities that occur during the dose escalation phase
Time Frame:Approximately 4-6 months
Safety Issue:
Description:Threshold and MD Anderson Cancer Center to evaluate patient safety data to determine proper dose
Measure:Number of participants with treatment related adverse events
Time Frame:Approximately 2 years
Safety Issue:
Description:Safety grading based on CTCAE guidelines
Measure:Change from tumor diameter baseline
Time Frame:Approximately 2 years
Safety Issue:
Description:Antitumor efficacy based on irRECIST

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Threshold Pharmaceuticals

Trial Keywords

  • Immunotherapy
  • Hypoxia
  • Evofosfamide
  • Ipilimumab
  • TH-302

Last Updated