Description:
This phase I trial studies the side effects and how well tremelimumab and durvalumab work in
treating patients with colorectal cancer that has spread to the liver and can be removed by
surgery. Immunotherapy with monoclonal antibodies, such as tremelimumab and durvalumab, may
help the body's immune system attack the cancer, and may interfere with the ability of tumor
cells to grow and spread.
Title
- Brief Title: Tremelimumab (Anti-CTLA-4) Plus MEDI4736 (Anti-PD-L1) in Resectable Colorectal Cancer Liver Metastases
- Official Title: Pilot Study Assessing the Safety and Tolerability of the Neoadjuvant Use of Tremelimumab (Anti-CTLA-4) Plus MEDI4736 (Anti-PD-L1) in the Treatment of Resectable Colorectal Cancer Liver Metastases
Clinical Trial IDs
- ORG STUDY ID:
2015-0828
- SECONDARY ID:
NCI-2016-00772
- NCT ID:
NCT02754856
Conditions
- Colorectal Cancer
- Liver Metastases
Interventions
| Drug | Synonyms | Arms |
|---|
| Tremelimumab | | Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab |
| Fluorouracil | 5-Fluorouracil, 5-FU, Adrucil, Efudex | Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab |
| Leucovorin | Citrovorum, Wellcovorin | Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab |
| Oxaliplatin | Eloxatin | Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab |
| Bevacizumab | Avastin, Anti-VEGF monoclonal antibody | Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab |
| MEDI4736 | Durvalumab | Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab |
Purpose
The goal of this clinical research study is to learn if tremelimumab in combination with
MEDI4736, FOLFOX (fluorouracil, leucovorin, and oxaliplatin), and bevacizumab can help to
control colorectal cancer that has spread to the liver. The safety of these drugs will also
be studied.
Detailed Description
Study Drug Administration:
If participant is found to be eligible to take part in this study, they will receive FOLFOX
and bevacizumab by vein over about 2 days during Weeks 1, 3, 5, and 7.
Participant will also receive tremelimumab by vein over about 1 hour and MEDI4736 by vein
over about 4 hours during Week 11. After Week 11, participant will receive MEDI4736 alone by
vein over about 1 hour during Weeks 21, 25, 29, and 33.
Between Weeks 15 and 17, participant will have their already scheduled liver surgery. This
means participant will receive FOLFOX, bevacizumab, and tremelimumab before their surgery
and MEDI4736 after their surgery.
Study Visits:
During Week 1:
- Participant will have a physical exam.
- Blood (about 6 tablespoons) will be drawn for routine tests and for testing related to
participant's immune system.
- If participant can become pregnant, part of the above routine blood sample will be used
for a pregnancy test. Urine may also be collected for this test.
During Weeks 3, 5, and 7:
- Blood (about 1 tablespoon) will be drawn for routine tests.
- During Week 5, participant will have a physical exam.
Between Weeks 9 and 11:
- Blood (about 4 tablespoons) will be drawn for tests related to the immune system.
- Participant will have a CT scan.
- Participant will have a liver tumor biopsy to check the status of the disease and for
biomarker testing. To perform a tumor tissue biopsy, the affected area is numbed with
anesthetic and a small amount of tissue is removed with a small needle. Participant
will also receive anesthesia before the procedure. This will be discussed with
participant in more detail before the biopsy.
During Week 11:
- Participant will have a physical exam.
- Blood (about 4 teaspoons) will be drawn for routine tests.
- If participant can become pregnant, part of the above routine blood sample will be used
for a pregnancy test. Urine may also be collected for this test.
During Week 15:
- Participant will have a physical exam.
- Blood (about 5 tablespoons) will be drawn for routine tests and tests related to
participant's immune system.
- Participant will have a CT scan.
Between Weeks 15 and 17, participant will have liver surgery as part of their standard care.
Participant will sign a separate consent form for this procedure.
During Weeks 19:
- Participant will also have a physical exam.
- Blood (about 7 tablespoons) will be drawn for routine tests, to check the status of the
disease, and for tests related to participant's immune system.
During Week 21:
- Participant will have a physical exam.
- Blood (about 4 teaspoons) will be drawn for routine tests.
- If participant can become pregnant, part of the above routine blood sample will be used
for a pregnancy test. Urine may also be collected for this test.
During Week 25:
- Participant will have a physical exam.
- Blood (about 4 teaspoons) will be drawn for routine tests.
During Weeks 29, 44, and 68:
- Participant will have a physical exam.
- Blood (about 8 teaspoons) will be drawn for routine tests and to check the status of
the disease.
- Participant will have a CT scan or MRI.
During Week 33:
- Participant will have a physical exam.
- Blood (about 6 tablespoons) will be drawn for routine tests and tests related to
participant's immune system.
During Week 56:
- Participant will have a physical exam.
- Blood (about 7 tablespoons) will be drawn for routine tests, to check the status of the
disease, and for tests related to participant's immune system.
- Participant will have a CT scan.
Length of Study:
Participant may receive FOLFOX and bevacizumab during Weeks 1, 3, 5, and 7. Participant may
receive tremelimumab and MEDI4736 for 1 week and MEDI4736 alone for up to an additional 4
weeks. Participant will no longer be able to take the study drugs if the disease gets worse,
if intolerable side effects occur, or if they are unable to follow study directions.
Patient's participation on this study will be over after follow-up.
Follow-Up:
If participant stops treatment for any reason, they will be asked to come to the hospital so
their study doctor may check their health and follow up any ongoing side effects or
discomfort until they get better.
If the disease has gotten better or remained the same, participant's doctor will continue to
check on the status of the disease as part of their standard of care, which may include
imaging scans and/or blood draws for routine tests.
Follow-up will continue for 1½ years or until participant withdraws from the study.
This is an investigational study. MEDI4736 and tremelimumab are not FDA approved or
commercially available. They are currently being used for research purposes only. FOLFOX and
bevacizumab are FDA approved and commercially available for the treatment of colorectal
cancer.
The study doctor can explain how the study drugs are designed to work.
Up to 35 participants will take part in this study. All will be enrolled at MD Anderson.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Tremelimumab + MEDI4736 + FOLFOX + Bevacizumab | Experimental | Participants receive FOLFOX (Fluorouracil, Leucovorin, and Oxaliplatin), and Bevacizumab by vein over about 2 days during Weeks 1, 3, 5, and 7.
Participants also receive Tremelimumab by vein over about 1 hour and MEDI4736 by vein over about 4 hours during Week 11. After Week 11, participants receives MEDI4736 alone by vein over about 1 hour during Weeks 21, 25, 29, and 33.
Between Weeks 15 and 17, participant undergoes scheduled liver surgery. | - Tremelimumab
- Fluorouracil
- Leucovorin
- Oxaliplatin
- Bevacizumab
- MEDI4736
|
Eligibility Criteria
Inclusion Criteria:
1. Patients must have histologically or cytologically confirmed colorectal cancer with
metastases deemed resectable by a general or liver surgeon (resectability may involve
the use of ablative techniques to some but not all liver metastases). Those patients
with known disease outside of the liver are not eligible (except for patients with
primary lesions in place that are planned for resection or nonspecific lung
metastases <1cm).
2. Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
=/>10 mm with spiral CT scan.
3. All lines of prior therapy accepted. Subjects with prior hepatic or extra-hepatic
resections of metastatic disease will be included.
4. Age =/>18 years. Because no dosing or adverse event data are currently available on
the use of tremelimumab in combination with MEDI4736 in patients <18 years of age,
children are excluded from this study.
5. Life expectancy of greater than 6 months.
6. ECOG performance status =/<1 (Karnofsky =/>70%).
7. Patients must have normal organ and marrow function as defined: a) leukocytes
=/>3,000/mcL; b) absolute neutrophil count =/>1,500/mcL; c) platelets =/>100,000/mcL;
d) total bilirubin < 1.5 X institutional normal limits (subjects with known Gilbert
syndrome are eligible with total bilirubin < 3.0 mg/dL); e) AST(SGOT)/ALT(SGPT) =/< 3
X institutional upper limit of normal; f) creatinine within normal institutional
limits OR g) creatinine clearance =/>60 mL/min/1.73 m^2 for patients with creatinine
levels above institutional normal.
8. Known MSI, BRAF, and KRAS status.
9. The effects of tremelimumab and/or MEDI4736 on the developing human fetus at the
recommended therapeutic dose are unknown. For this reason and because immune
checkpoint inhibitors as well as other therapeutic agents used in this trial are
known to be teratogenic, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, for the duration of study participation, and 180 days after the
last dose of tremelimumab. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.
10. Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
1. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier. An exception to this criterion is if patients
are enrolled after the completion of neoadjuvant chemotherapy. If this is the case
then 2 weeks must elapse prior to the beginning of immune checkpoint therapy.
2. Patients may not be receiving any other investigational agents.
3. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], celiac disease, systemic lupus erythematosus,
Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'
disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are
exceptions to this criterion: a) Patients with vitiligo or alopecia; b) Patients with
hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement; c)
Any chronic skin condition that does not require systemic therapy; d) Patients
without active disease in the last 5 years may be included but only after
consultation with the study physician.
4. Subjects with a condition requiring systemic treatment with either corticosteroids
(>10mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids and adrenal
replacement doses > 10mg daily prednisone equivalents are permitted in the absence of
active autoimmune disease.
5. Prior exposure to T cell checkpoint inhibitor therapies.
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.
7. Positive test for hepatitis B virus surface antigen or hepatitis C (IgG or RNA test)
indicating acute or chronic infection.
8. Positive test for HIV.
9. Women who are pregnant, which includes women with a positive pregnancy test at
enrollment or prior to the administration of study medication, or breastfeeding are
not allowed on study.
10. Receipt of a live vaccine within 30 days of study entry.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Feasibility of Tremelimumab plus MEDI4736 with FOLFOX and Bevacizumab in Candidates for Resection of Colorectal Cancer Liver Metastases |
| Time Frame: | 15 weeks |
| Safety Issue: | |
| Description: | Feasibility assessed by whether or not the patient successfully goes to surgery following the planned treatments, scans, and biopsy. Combination regimen considered feasible if at least 80% of patients successfully undergo surgery. It will be infeasible if fewer than 60% of patients can undergo surgery. |
Secondary Outcome Measures
| Measure: | Relapse-free survival (RFS) of Tremelimumab plus MEDI4736 with FOLFOX and Bevacizumab in Candidates for Resection of Colorectal Cancer Liver Metastases |
| Time Frame: | 56 weeks |
| Safety Issue: | |
| Description: | Relapse-free survival (RFS) assessed from the date of study entry until relapse or death from any cause. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | M.D. Anderson Cancer Center |
Trial Keywords
- Colorectal Cancer
- Liver Metastases
- Resectable liver metastases
- Tremelimumab
- Fluorouracil
- 5-Fluorouracil
- 5-FU
- Adrucil
- Efudex
- Leucovorin
- Citrovorum
- Wellcovorin
- Oxaliplatin
- Eloxatin
- Bevacizumab
- Avastin
- Anti-VEGF monoclonal antibody
- MEDI4736
- Durvalumab
Last Updated
March 29, 2017
