MC# 16-03 - A Phase Ib Study of an Immunotherapeutic Vaccine, DPX-Survivac with Low Dose Cyclophosphamide and Epacadostat (INCB024360) in Patients with Recurrent Ovarian Cancer.

  • Agent(s): DPX-Survivac, Epacadostat
  • Disease Type(s): Ovarian
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Immunotherapy
  • Molecular Target(s): IDO1/2

Mechanism of Action

  • DPX-Survivac is an immunotherapeutic vaccine that targets survivin, a member of the inhibitor of apoptosis protein family, to initiate apoptosis.

  • Epacadostat is a novel, potent, and selective inhibitor of the enzyme IDO1, which, when inhibited, prevents the catabolism of tryptophan and may restore antitumor cell-mediated immune responses.

Purpose

In this study, the sponsor and investigators want to learn:

  • If DPX-Survivac, when given with Cyclophosphamide and Epacadostat, prevents or delays tumor growth or shrinks an existing tumor

  • If DPX-Survivac, when given with Cyclophosphamide and Epacadostat, has an effect on a participant’s cancer, by measuring substances in the blood and tumor tissue produced or changed by the cancer (“biomarkers”)

  • The effects of the study agent when given with Cyclophosphamide and Epacadostat

  • If research tests can be used in the future to predict who will benefit from DPX-Survivac

Inclusion Criteria
  • Histologically confirmed stage IIc-IV epithelial ovarian, fallopian tube or peritoneal cancer. (Histologic documentation of the original primary tumor is required via pathology report.)

  • Completed first-line treatment (debulking surgery and adjuvant or neoadjuvant treatment with standard of care treatment such as carboplatin and paclitaxel). Platinum-resistant and platinum-sensitive are defined as progression after initial chemotherapy between 3 and 6 months (inclusive) or greater than 6 months respectively. Subjects may have had any number of subsequent lines of chemotherapy.

  • Must have had a complete or partial response (CR or PR) by radiological imaging to their most recent standard of care chemotherapy treatment. The most recent systemic  therapy must have been platinum based.

  • Must have evidence of progressive disease with either rising CA-125 (rising CA-125 must be confirmed by two measurements at least 2 weeks apart and be greater than a normal reference value of 35 units) and/or radiologic progression. Current progression must be at least 3 months after the completion of most recent standard therapy. (Patients with rapidly progressive tumors are not suitable candidates for immunotherapy.)

  • Subjects must have measurable disease, successfully complete a pre-treatment tumor biopsy, and be willing to undergo tumor biopsy during treatment. Sum of baseline target lesions by RECIST v1.1 must be less than 5 cm. Subjects with only one measurable disease lesion that is required for biopsy (i.e. no other biopsiable lesions) are not eligible.

  • Females age ≥ 18 years old of any racial or ethnic group

  • Must be ambulatory with an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

  • Life expectancy ≥ 6 months

  • Laboratory Requirements:

    • White blood cell > 2,500/ mcL (> 2.5 x 109/L)

    • Absolute neutrophil count > 1,000/ mcL (> 1 x 109/L)

    • Platelet count > 75,000/ mcL (> 75 x 109/L)

    • Hemoglobin ≥ 8 g/dL (≥ 80 g/L) (subjects who have received a transfusion or erythropoietin up to one week prior to receiving the first dose of cyclophosphamide are eligible for the study)
    • International normalized ration (INR) or prothrombin time (PT) < 1.5 x ULN (upper limit of normal)

    • Activated partial thromboplastin time (aPTT) < 1.5 x ULN

    • Serum creatinine < 1.5 x ULN

    • Total bilirubin < 2.0 x ULN

    • ALT and AST < 2.5 x ULN

    • Subjects with bone metastases and no hepatic parenchymal metastases on screening radiographic examinations may enroll if alkaline phosphatase is < 5.0 x ULN

  • Ability to understand and provide a signed informed consent from (ICF) approved by the Institutional Review Board / Research Ethics Board (IRB/REB).

  • Ability to comply with protocol requirements.

Exclusion Criteria
  • Patients eligible for otherwise curative treatment.

  • Patients undergoing concurrent chemotherapy, radiation therapy, immunotherapy or who are currently on an investigational product/study are excluded. There must be at least 21  days (or 3 half-lives in the case of treatment involving monoclonal antibody such as Avastin) since completion of prior chemotherapy, radiation or antibody-based immunotherapy until study treatment begins (study day 0). Patients must have recovered from all acute toxicities from prior treatment: peripheral neuropathy must be < grade 2.

  • Patients who have received prior survivin based vaccines are excluded.

  • Subjects who have received prior immune checkpoint inhibitors (e.g. anti–CTLA-4, anti– PD-1, anti–PD-L1, or any other antibody or drug specifically targeting T cell co-stimulation) or an IDO inhibitor are excluded. Subjects who have received experimental vaccines or other immune therapies should be discussed with the medical monitor to determine eligibility.

  • Concurrent (within the last 5 years) second malignancy other than non-melanoma skin cancer, cervical carcinoma in situ, or controlled bladder cancer.
  • Clinical ascites (Clinical ascites is defined as accumulated abdominal fluid with associated clinical symptoms. Asymptomatic ascites that is only visible by radiologic imaging is not exclusionary).

  • Subjects with sum of baseline target lesions greater than or equal to 4 cm (by RECIST v1.1).

  • Malignant bowel obstruction.

  • History of autoimmune disease, such as but not restricted to, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis requiring treatment within the last two years.  Patients with vitiligo or diabetes are not excluded.

  • Patients with recent history of thyroiditis. Subjects with a remote history (greater than 5 years) of thyroiditis are not excluded.

  • Presence of a serious acute infection requiring antibiotic treatment within 21 days of study day 0.

  • Chronic infection including but not limited to: urinary tract infection, syphilis (Treponema pallidum), human immunodeficiency virus (HIV), or antigen positive viral hepatitis (as determined by Hepatitis B surface antigen and Hepatitis C serology).

  • Patients with known active central nervous system (CNS) or leptomeningeal metastasis (brain metastases). Patients with treated brain metastasis are not excluded if they are off steroids, are 28 days from completion of therapy, a follow-up scan does not show progressive disease in CNS, and they are asymptomatic or have stable symptoms.

  • GI condition that might limit absorption of oral agents.

  • Serious intercurrent chronic or acute illness, such as cardiac disease (New York Heart Association class III or IV), hepatic disease, or other illness considered by the investigator as an unwarranted high risk for an investigational product.

  • Patients on steroid therapy or other immunosuppressive, such as azathioprine or cyclosporin

  • Patients who have discontinued any steroids 35 days prior to study day 0 (except that used as pre-medication for chemotherapy or contrast-enhanced studies) are eligible. Subjects may be on physiologic doses of replacement prednisone or equivalent doses of corticosteroid (<10 mg daily). Short term use of steroids for asthma or chronic obstructive pulmonary disorder (COPD) exacerbation is acceptable.

  • Patients receiving monoamine oxidase inhibitors (MAOIs) or a drug which has significant MAOI activity (e.g. meperidine, linezolid, methylene blue) are excluded. Subjects must discontinue MAOI by study day -1.

  • Patients receiving any UGT1A9 inhibitor (e.g. diclofenac, imipramine, ketoconazole, mefenamic acid, and probenecid) 28 days prior to study day 0 are excluded.

  • Acute or chronic skin and/or microvascular disorders that will interfere with subcutaneous injection of the vaccine or subsequent assessment of potential skin reactions.

  • Edema or lymphedema in the lower limbs > grade 1.

  • Allergies to any vaccine, that after discussion with IMV, are serious enough to warrant exclusion from this study.

  • Known allergy or reaction to any component of the cyclophosphamide or epacadostat drug formulations (as applicable).
  • Pregnant or nursing mothers. Or women with the potential to become pregnant not using acceptable methods of birth control.
  • Patients with a medical or psychological impediment to probable compliance with the protocol should be excluded.

  • Active drug or alcohol use or dependence or other conditions that, in the opinion of the investigator, would interfere with adherence to study requirements. Social alcohol use is acceptable.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT02785250

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Re: MC# 16-03