Durvalumab, MVA-BN-CV301, FPV Vaccine CV301, and Capecitabine with or without Bevacizumab in Treating Patients with Metastatic Colorectal or Pancreatic Cancer
- Histologically proven metastatic pancreatic or colorectal adenocarcinoma with measurable disease, defined as at least 1 unidimensionally measurable lesion on a computed tomography (CT) scan as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- Stable on, or responding to 1st line therapy for metastatic disease * Radiographically (RECIST 1.1) confirmed stable or responding disease for at least 8, and not more than 16 weeks from the initiation of 1st line therapy for metastatic disease * Due to the timing of enrollment, patients who have completed a maximum of 16 weeks of 1st line chemotherapy may be enrolled > 16 weeks after initiation of 1st line therapy if disease stability/response (without additional intervening therapy) can be documented within 4 weeks prior to first dose of CV301
- 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
- Disease that is amenable to serial biopsies
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Blood pressure < 160/100 mmHg
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelets >= 100,000/mm^3
- Hemoglobin >= 9.0 g/dL
- Serum creatinine =< 1.5 X upper normal limit of institution's normal range OR creatinine clearance >= 40 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal; creatinine clearance should be determined by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
- Aspartate aminotransferase (AST) and alanine aminotransferase (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
- 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
- Life expectancy > 12 weeks
- Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to initiation of treatment AND confirmed prior to initiation of treatment on day 1
- Alternatively, female subjects must be of non-reproductive potential (i.e., 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)
- 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
- Any prior immunotherapy or vaccine therapy
- 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, Sjogren’s syndrome, auto-immune Bell’s palsy, Guillain-Barre 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 principal investigator
- Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and TNFalpha 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
- 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 * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
- Positive test for human immunodeficiency virus (HIV) infection
- Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) * 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 hepatitis B virus [HBV] viral load by polymerase chain reaction [PCR]) are eligible
- Active hepatitis C * Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV ribonucleic acid (RNA)
- Active tuberculosis OR known history of previous clinical diagnosis of tuberculosis
- 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
- Signs or symptoms of infection within 2 weeks prior to week 1, day 1
- Received oral or IV antibiotics within 2 weeks prior to week 1, day 1 * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
- Prior allogeneic bone marrow transplantation or prior solid organ transplantation
- 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 * Influenza vaccination should be given during influenza season only; patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to week 1, day 1 or at any time during the study
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- 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 * o Herbal therapy intended as anti-cancer therapy must be discontinued at least 1 week before week 1, day 1
- Central nervous system (CNS) metastases including a history of leptomeningeal carcinomatosis
- Subjects with uncontrolled seizures
- 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 principal investigator
- Cardiovascular disease including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months
- Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia’s correction
- Life-threatening visceral disease or other severe concurrent disease
- Grade >= 2 proteinuria at screening (or known prior)
- 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
- Patients concurrently receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab or any excipient or any egg products
- 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
District of Columbia
I. To determine the 8.5 month progression free survival rate (PFS8.5mos) of durvalumab plus CV301 in combination with maintenance capecitabine and bevacizumab in patients with metastatic colorectal cancer, whose disease is stable on, or responding to first (1st) line therapy for metastatic disease. (Colorectal Cancer Arm)
II. To determine the progression free survival rate (PFS4mos) of durvalumab plus CV301 in combination with maintenance capecitabine in patients with metastatic pancreatic cancer, whose disease is stable on, or responding to 1st line therapy for metastatic disease. (Pancreatic Cancer Arm)
I. To determine, in patients treated with durvalumab plus CV301 whose disease is stable on, or responding to 1st line therapy for metastatic colorectal or pancreatic cancer: objective response rate (ORR) and duration of response, progression free survival (PFS), overall survival (OS), disease control rate (DCR) defined as ORR + rate of stable disease at 4 months), tolerability and safety of the combination.
II. To assess the predictive value of immune-inhibitory proteins, including PD-1, PD-L1 (B7H1), B7H3, B7H4, IDO, and arginase; and to assess the characteristics of the infiltrating T-cells in tumor samples.
III. Using a flow-based assay, to determine the number of immune cell subsets from peripheral blood mononuclear cell (PBMC) at baseline and during treatment and attempt to identify a pattern correlating with clinical benefit.
IV. To evaluate the antigen-specific T-cell activation against the target antigens of the vaccine, MUC-1 and carcinoembryonic antigen (CEA) as well as other potential cascade antigens, including but not limited to brachyury.
V. To evaluate serum soluble factors and serum cytokine expression profiles at baseline and on treatment and determine correlates of clinical benefit.
VI. To evaluate the relationship between tumor mutation burden and clinical benefit.
VII. To evaluate the expansion of peripheral and, potentially, intratumoral T cell clones as correlates and identify correlation with clinical benefit.
EXPLORATORY SCIENTIFIC OBJECTIVES:
I. To assess, in patient tumor samples, the predictive value, and the changes in response to treatment of immune-inhibitory proteins and other cell signaling pathways as measured by reverse phase phosphoprotein pathway analysis of the laser capture microdissected tumor epithelium and tumor stroma/immune cell compartments.
II. To develop ex vivo models of patient tumors derived from patient tumor samples.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive prime cancer vaccine MVA-BN-CV301 subcutaneously (SC) on days 1 and 29. Starting weeks 3, patients receive durvalumab intravenously (IV) over 1 hour every 2 weeks and capecitabine orally (PO) twice daily (BID) 5 days per week in the absence of disease progression or unacceptable toxicity. Patients may stop capecitabine by week 52 if achieve complete response. Patients also receive FPV vaccine CV301 SC on day 1 of weeks 9, 13, 17, 21, 25, and 37, and every 24 weeks starting week 53 in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive prime cancer vaccine MVA-BN-CV301 SC on days 1 and 29. Starting weeks 3, patients receive durvalumab IV over 1 hour every 2 weeks, capecitabine PO BID 5 days per week, and bevacizumab IV every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients may stop capecitabine and bevacizumab by week 52 if achieve complete response. Patients also receive FPV vaccine CV301 SC on day 1 of weeks 9, 13, 17, 21, 25, and 37, and every 24 weeks starting week 53 in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 12 weeks for up to 12 months.
Trial Phase Phase II
Trial Type Treatment
MedStar Georgetown University Hospital
Benjamin Adam Weinberg
- Primary ID 2017-1189
- Secondary IDs NCI-2017-02486
- Clinicaltrials.gov ID NCT03376659