Colorectal Adenocarcinoma, Metastatic Colorectal Cancer, Metastatic Pancreatic Cancer, Pancreatic Adenocarcinoma
Conditions
Keywords
PD-L1
Brief summary
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.
Interventions
DRUGDurvalumab
750mg IV q2 weeks
BIOLOGICALCV301
MVA-BN-CV301 (prime) - two priming doses of 1.6 x 109 infectious units/0.5 mL (Inf.U) given subcutaneously (s.c.) FPV-CV301 (boost) - dosed at 1 × 109 Inf.U/0.5 mL given s.c.
DRUGCapecitabine
1000mg orally twice a day, Monday - Friday Weekly
DRUGBevacizumab
5mg/kg IV q2weeks
Sponsors
Mayo Clinic
Indiana University
Emory University
National Cancer Institute (NCI)
George Mason University
Thomas Jefferson University
MedImmune LLC
Bavarian Nordic
Georgetown University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase II Dose of Durvalumab | 6 months | The Recommended Phase II dose of durvalumab in the combination of durvalumab plus CV301 with maintenance chemotherapy as determined by the Phase I design |
| Progression Free Survival (PFS) Colorectal Cancer | 24 months | To determine the progression free survival (PFS) 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 1st line therapy for metastatic disease |
| Progression Free Survival (PFS) Pancreatic Cancer | 24 months | To determine the progression free survival rate (PFS) 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 4 months | DCR is defined as the proportion of patients with a documented CR, PR, or SD at 4 months according to the RECIST version 1.1. |
| Objective Response Rate (ORR) | 1 year | ORR is defined as the proportion of patients whose best overall response recorded during treatment is either CR or PR according to the RECIST version 1.1. |
| Duration of Response | 1 year | The duration of response will also be captured as the time from which a response was first identified, until progression of disease according to the RECIST version 1.1 (or death due to any cause). |
| Tolerability and Safety of the Combination | 2 years | Tolerability and safety of the combination as determined by the number of patients with treatment emergent adverse events |
| Progression Free Survival (PFS) | 24 months | PFS is defined as the time from consenting to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first. |
| Overall Survival (OS) | 4 years | To determine overall survival, subjects will be followed from time of consent until death (or until study termination). Subject will be followed for survival after discontinuing study medication and after the adverse event collection period has ended. |
Countries
United States
Participant flow
Pre-assignment details
Study terminated during Phase I. No subjects enrolled in Phase II.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Safety- All Groups * MVA-BN-CV301 (prime) - Day 1 and Day 29.
* FPV-CV301 (boost) - Day 1 of Weeks 9, 13, 17, 21, 25, 37, and q24 weeks starting week 53.
* Durvalumab - q2 weeks
* Capecitabine - twice a day, Monday - Friday Weekly
* Bevacizumab - q2weeks (colorectal cancer patients only)
Durvalumab: 750mg IV q2 weeks
CV301: MVA-BN-CV301 (prime) - two priming doses of 1.6 x 109 infectious units/0.5 mL (Inf.U) given subcutaneously (s.c.)
FPV-CV301 (boost) - dosed at 1 × 109 Inf.U/0.5 mL given s.c.
Capecitabine: 1000mg orally twice a day, Monday - Friday Weekly
Bevacizumab: 5mg/kg IV q2weeks | 8 |
| Total | 8 |
Baseline characteristics
| Characteristic | Phase I - Safety- All Groups |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 |
Outcome results
Primary
Progression Free Survival (PFS) Colorectal Cancer
To determine the progression free survival (PFS) 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 1st line therapy for metastatic disease
Time frame: 24 months
Population: colorectal cancer
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Safety | Progression Free Survival (PFS) Colorectal Cancer | 7.4 months |
Primary
Progression Free Survival (PFS) Pancreatic Cancer
To determine the progression free survival rate (PFS) 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
Time frame: 24 months
Population: pancreatic cancer
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Safety | Progression Free Survival (PFS) Pancreatic Cancer | 4.5 months |
Primary
Recommended Phase II Dose of Durvalumab
The Recommended Phase II dose of durvalumab in the combination of durvalumab plus CV301 with maintenance chemotherapy as determined by the Phase I design
Time frame: 6 months
Population: Phase 1 not completed because study terminated due to lack of enrollment. Recommended phase II dose could not be determined.
Secondary
Disease Control Rate (DCR)
DCR is defined as the proportion of patients with a documented CR, PR, or SD at 4 months according to the RECIST version 1.1.
Time frame: 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Safety | Disease Control Rate (DCR) | 5 Participants |
Secondary
Duration of Response
The duration of response will also be captured as the time from which a response was first identified, until progression of disease according to the RECIST version 1.1 (or death due to any cause).
Time frame: 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase I - Safety | Duration of Response | 145 days |
Secondary
Objective Response Rate (ORR)
ORR is defined as the proportion of patients whose best overall response recorded during treatment is either CR or PR according to the RECIST version 1.1.
Time frame: 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Safety | Objective Response Rate (ORR) | 2 Participants |
Secondary
Overall Survival (OS)
To determine overall survival, subjects will be followed from time of consent until death (or until study termination). Subject will be followed for survival after discontinuing study medication and after the adverse event collection period has ended.
Time frame: 4 years
Population: number of subjects still alive at the end of the study follow up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Safety | Overall Survival (OS) | 1 Participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from consenting to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first.
Time frame: 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I - Safety | Progression Free Survival (PFS) | 4.7 months |
Secondary
Tolerability and Safety of the Combination
Tolerability and safety of the combination as determined by the number of patients with treatment emergent adverse events
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I - Safety | Tolerability and Safety of the Combination | 8 Participants |