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.
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.
