Durvalumab Plus CV301 With Maintenance Chemotherapy in Metastatic Colorectal or Pancreatic Adenocarcinoma

A Phase I/II Trial of the PD-L1 Inhibitor, Durvalumab Plus CV301 in Combination With Maintenance Chemotherapy for Patients With Metastatic Colorectal or Pancreatic Adenocarcinoma

This is a dual arm, open label phase I/II study to evaluate the safety and clinical activity of the combination of durvalumab with CV301 in combination with maintenance chemotherapy for patients with metastatic colorectal or pancreatic cancer whose disease is stable on, or responding to 1st line therapy for metastatic disease. Patients with metastatic colorectal or pancreatic adenocarcinoma who still have an adequate performance status and normal hepatic and renal function will be eligible.

Inclusion Criteria:

1. Histologically proven metastatic pancreatic or colorectal adenocarcinoma with measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1 criteria.

2. Stable on, or responding to 1st line therapy for metastatic disease

   1. At least 8 and not more than 16 weeks after initiating 1st line therapy for metastatic disease
   2. Tumor stability/response on 1st line therapy will be determined as per RECIST 1.1

3. Prior adjuvant chemotherapy is allowed, as long as a minimum of 3 months (for pancreatic cancer) and 6 months (for colorectal cancer) has passed between the completion of adjuvant therapy and the start of first line therapy

4. Disease that is amenable to serial biopsies

5. ECOG performance status 0-1

6. Age >= 18 years

7. Blood pressure <160/100 mmHg

8. Adequate hepatic, bone marrow, and renal function:

   1. Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin ≥ 9.0 g/dL

   2. Renal function: Serum creatinine ≤ 1.5 X upper normal limit of institution's normal range OR creatinine clearance ≥ 40 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal. Creatinine clearance should be determined by the Cockcroft-Gault formula (below) or by 24-hour urine collection for determination of creatinine clearance:

      Males:

      Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)

      Females:

      Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL)

   3. Hepatic function: AST and ALT ≤ 2.5 X the upper normal limit of institution's normal range. Non-fasting bilirubin ≤ 1.5 X the upper normal limit of institution's normal range.

9. Partial Thromboplastin Time (PTT) must be ≤ 1.5 X upper normal limit of institution's normal range and INR (International Normalized Ratio) ≤ 1.5. Subjects on anticoagulant (such as coumadin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator. Due to the drug-drug interaction between warfarin and capecitabine, alternate anticoagulation should be considered.

10. Life expectancy > 12 weeks.

11. Women of childbearing potential must have a negative serum or urine pregnancy test within 28 days prior to initiation of treatment AND confirmed prior to initiation of treatment on Day 1.

12. Alternatively, female subjects must be of non-reproductive potential (ie, post-menopausal by history: ≥60 years old and no menses for ≥1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy).

13. Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consents, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures.

Exclusion Criteria:

1. Any prior immunotherapy or vaccine therapy

2. History of active or prior documented autoimmune disease within the past 2 years including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, auto-immune Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis, with the following caveats:

   • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
   • Patients with Grave's disease, vitiligo, autoimmune alopecia, or psoriasis not requiring systemic treatment (within the past 2 years) are eligible upon consultation with the Study Chairs
   • Patients with questionable diagnosis of autoimmune disease who have never been treated with immunosuppressive regimen and have no ongoing symptoms at the time of enrollment may be eligible after discussion with medical monitor and principle investigator

3. Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and TNFα antagonists) within 28 days prior to Week 1, Day 1

   • Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the Study Co-chairs.
   • The use of inhaled, intranasal, ophthalmic or topical corticosteroids is allowed
   • The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension is allowed.
   • Physiologic doses of systemic corticosteroids at doses which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
   • High dose steroid pre-treatment for CT contrast dye allergy is allowed, provided the dose(s) of steroids is(are) given at least 1 week prior to starting the study medications

4. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan

   o History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

5. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

6. Positive test for HIV infection

7. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening)

   o Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg test and a positive IgG antibody to hepatitis B core antigen [anti-HBc] OR negative HBV viral load by PCR) are eligible.

8. Active hepatitis C

   o Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.

9. Active tuberculosis OR known history of previous clinical diagnosis of tuberculosis

10. Severe infections within 4 weeks prior to Week 1, Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia

    o Any course of oral or IV antibiotics must have been completed at least 2 weeks prior to the first dose of study medications

11. Signs or symptoms of infection within 2 weeks prior to Week 1, Day 1

12. Received oral or IV antibiotics within 2 weeks prior to Week 1, Day 1

    o Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.

13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

14. Administration of a live, attenuated vaccine within 30 days before Week 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study

    o Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine (e.g., FluMistTM) within 4 weeks prior to Week 1, Day 1 or at any time during the study.

15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

16. Any anti-cancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 2 weeks prior to initiation of study treatment, with the following exceptions:

    • Hormone-replacement therapy or oral contraceptives
    • Herbal therapy > 1 week before Week 1, Day 1 (herbal therapy intended as anti-cancer therapy must be discontinued at least 1 week before Week 1, Day 1)

17. CNS metastases including a history of leptomeningeal carcinomatosis

18. Subjects with uncontrolled seizures

19. The subject has had another active malignancy within the past five years except for cervical cancer in situ, in situ carcinoma of the bladder or non-melanoma carcinoma of the skin. Questions regarding the inclusion of individual subjects should be directed to the Principle Investigator.

20. Cardiovascular disease including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months

21. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction

22. Life-threatening visceral disease or other severe concurrent disease

23. Grade ≥2 proteinuria at screening (or known prior)

24. Women who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing two highly effective and acceptable forms of contraception throughout their participation in the study and for 90 days after last dose of study drug.

25. Patients concurrently receiving any other investigational agents.

26. History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab or any excipient or any egg products

27. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.