Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal Cancer
Study Details
Study Description
Brief Summary
The purpose of this study is to find out what effects, good and/or bad, MEDI4736 has on the patient and cancer.
MEDI4736 is a type of medication called an antibody. Antibodies are normal proteins in the body that help fight infections and possibly cancer. MEDI4736 is a special type of an antibody produced in a laboratory. MEDI4736 works by blocking a specific protein called the Programmed Death Ligand-1 (PDL-1), located on tumor cells.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Patients with Advanced Colorectal Cancer This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments. |
Drug: MEDI4736
Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit.
|
Outcome Measures
Primary Outcome Measures
- Best Response Rate [2 years]
according to RECIST 1.1.
Secondary Outcome Measures
- Number of Participants Evaluated for Toxicities to Determine Safety [2 years]
Subjects will be evaluated for occurrence of AEs at each visit. Events will be characterized and reported. Safety will also be monitored by performing physical exams and routine laboratory procedures. Terminology Criteria for Adverse Events" V4.0 (CTCAE).
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Written informed consent obtained.
-
Histologically- or cytologically- confirmed CRC.
-
Microsatelite-high colorectal cancer (also known as MSI-H, DNA mismatch repair deficient, or sometimes Lynch syndrome); or increased Tumor-Infiltrating Lymphocytes in an archived tumor specimen or fresh biopsy.
-
Locally advanced or metastatic CRC
-
Subjects have received two or more standard available therapies known to prolong survival and for which they would be considered eligible. At a minimum, such therapies should include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine (e.g., FOLFOX and FOLFIRI or their variants).
-
Age ≥ 18 years at time of study entry.
-
Eastern Cooperative Oncology Group (ECOG) status of 0 or 1
-
Adequate organ and marrow function as defined below:
-
Absolute neutrophil count ≥ 1,500/mm3.
-
Platelet count ≥ 90,000/mm3.
-
AST and ALT ≤ 3 × institutional upper limit of normal (ULN) or ≤ 5 × ULN for subjects with liver metastases.
-
Bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN for subjects with documented/suspected Gilbert's disease.
-
Serum creatinine ≤ 1.5 x ULN;
-
Radiographically measurable disease per RECIST 1.1.
-
Life expectancy ≥ 16 weeks.
-
Willingness to provide consent for use of archived tissue for research purposes.
-
Subjects will be required to agree to a biopsy performed at baseline and again at week 8 of the study in order to be eligible for enrollment in stage 1 of the study
-
Females of childbearing potential who are sexually active with a nonsterilized male partner must use 2 methods of effective contraception from screening, and must agree to continue using such precautions for 90 days after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control.
-
Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause).
-
Subjects must use 2 acceptable methods of effective contraception as described in below.
-
Nonsterilized males who are sexually active with a female partner of childbearing potential must use 2 acceptable methods of effective contraception from Day 1 and for 90 days after receipt of the final dose of investigational product.
Exclusion Criteria:
-
Anticancer therapy, monoclonal antibody or major surgery within 4 weeks prior to the first dose of MEDI4736.
-
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
-
Any prior Grade ≥ 3 irAE while receiving immunotherapy (including anti-CTLA-4 or anti-CD137 MAb) or any unresolved irAE of any grade (controlled irAE endocrinopathies are allowed).
-
Prior exposure to any anti-PD-1 or anti-PD-L1 antibody.
-
Current or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid.
-
Any unresolved toxicity CTCAE >Grade 2 from previous anti-cancer therapy.
-
Active autoimmune disease within the past 2 years, except for mild conditions not requiring systemic treatment, such as vitiligo.
-
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. NOTE: Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (e.g., by local ablation, surgery or radiotherapy).
-
Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, irritable bowel syndrome, ulcerative colitis).
-
Receipt of radiation therapy within 4 weeks prior to starting investigational product, or limited field of radiation for palliation within 2 weeks of the first dose of investigational product.
-
Known allergy or reaction to any component of the MEDI4736 formulation or its excipients.
-
Known central nervous system (CNS) metastases requiring treatment, such as surgery, radiation or steroids.
-
Known history of confirmed primary immunodeficiency.
-
History of organ transplant requiring therapeutic immunosuppression.
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Other malignancy within 3 years, except for noninvasive malignancies such as cervical carcinoma in situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ (DCIS) of the breast that has/have been surgically cured, or prior malignancy considered by the investigator to be of low likelihood for recurrence.
-
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any patient known to have active hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent.
-
Women who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
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Any other condition(s) that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
-
Subjects who are known to be HIV positive.
-
Receipt of live attenuated vaccination within 30 days prior to receiving MEDI4736
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
- MedImmune LLC
- AstraZeneca
Investigators
- Principal Investigator: Neil Segal, MD, PhD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 14-109
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Patients With Advanced Colorectal Cancer |
|---|---|
| Arm/Group Description | This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments. MEDI4736: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit. |
| Period Title: Overall Study | |
| STARTED | 16 |
| COMPLETED | 16 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Patients With Advanced Colorectal Cancer |
|---|---|
| Arm/Group Description | This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments. MEDI4736: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit. |
| Overall Participants | 16 |
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
57
|
| Sex: Female, Male (Count of Participants) | |
| Female |
3
18.8%
|
| Male |
13
81.3%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
6.3%
|
| Not Hispanic or Latino |
15
93.8%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
2
12.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
12
75%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
2
12.5%
|
| Region of Enrollment (Count of Participants) | |
| United States |
16
100%
|
Outcome Measures
| Title | Best Response Rate |
|---|---|
| Description | according to RECIST 1.1. |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Patients With Advanced Colorectal Cancer |
|---|---|
| Arm/Group Description | This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments. MEDI4736: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit. |
| Measure Participants | 16 |
| Complete Response |
1
6.3%
|
| Partial Response |
3
18.8%
|
| Stable Response |
4
25%
|
| Progression of Disease |
4
25%
|
| Not Entered |
4
25%
|
| Title | Number of Participants Evaluated for Toxicities to Determine Safety |
|---|---|
| Description | Subjects will be evaluated for occurrence of AEs at each visit. Events will be characterized and reported. Safety will also be monitored by performing physical exams and routine laboratory procedures. Terminology Criteria for Adverse Events" V4.0 (CTCAE). |
| Time Frame | 2 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Patients With Advanced Colorectal Cancer |
|---|---|
| Arm/Group Description | This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments. MEDI4736: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit. |
| Measure Participants | 16 |
| Count of Participants [Participants] |
16
100%
|
Adverse Events
| Time Frame | 2 years | |
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Patients With Advanced Colorectal Cancer | |
| Arm/Group Description | This will be a Simon two-stage design, single arm, phase II study. All subjects will receive MEDI4736 via IV infusion. Subjects will continue treatment for 12 months, or until progression of disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment occur. Following the 12-month treatment period, subjects without evidence for progressive disease or other reason to discontinue treatment will be monitored without further treatment. Upon evidence of PD (with or without confirmation according to RECIST 1.1) during the monitoring period, administration of MEDI4736 may resume at the Q2W schedule, for up to another 12 months. The same treatment guidelines followed during the initial 12-month treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same schedule of assessments. MEDI4736: Patients will be seen the day of administration of MEDI4736. A medical history, with particular reference to toxicities, including medication review, and physical examination will be conducted at each treatment visit. | |
All Cause Mortality |
||
| Patients With Advanced Colorectal Cancer | ||
| Affected / at Risk (%) | # Events | |
| Total | 7/16 (43.8%) | |
Serious Adverse Events |
||
| Patients With Advanced Colorectal Cancer | ||
| Affected / at Risk (%) | # Events | |
| Total | 8/16 (50%) | |
| Gastrointestinal disorders | ||
| Abdominal pain | 1/16 (6.3%) | |
| Diarrhea | 2/16 (12.5%) | |
| Nausea | 1/16 (6.3%) | |
| Small intestinal obstruction | 2/16 (12.5%) | |
| General disorders | ||
| Death NOS | 2/16 (12.5%) | |
| Fatigue | 3/16 (18.8%) | |
| Gait disturbance | 1/16 (6.3%) | |
| Non-cardiac chest pain | 1/16 (6.3%) | |
| Infections and infestations | ||
| Enterocolitis infectious | 1/16 (6.3%) | |
| Investigations | ||
| Blood bilirubin increased | 2/16 (12.5%) | |
| Metabolism and nutrition disorders | ||
| Anorexia | 1/16 (6.3%) | |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 2/16 (12.5%) | |
| Flank pain | 2/16 (12.5%) | |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
| Neoplasms ben/mal/unk (inc cyst/polyp) Other, spec | 1/16 (6.3%) | |
| Nervous system disorders | ||
| Tremor | 1/16 (6.3%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 2/16 (12.5%) | |
Other (Not Including Serious) Adverse Events |
||
| Patients With Advanced Colorectal Cancer | ||
| Affected / at Risk (%) | # Events | |
| Total | 16/16 (100%) | |
| Blood and lymphatic system disorders | ||
| Anemia | 2/16 (12.5%) | |
| Ear and labyrinth disorders | ||
| Ear pain | 1/16 (6.3%) | |
| Eye disorders | ||
| Blurred vision | 1/16 (6.3%) | |
| Gastrointestinal disorders | ||
| Diarrhea | 3/16 (18.8%) | |
| Dry mouth | 2/16 (12.5%) | |
| Nausea | 2/16 (12.5%) | |
| Abdominal pain | 1/16 (6.3%) | |
| Mucositis oral | 1/16 (6.3%) | |
| Vomiting | 1/16 (6.3%) | |
| General disorders | ||
| Fatigue | 7/16 (43.8%) | |
| Edema limbs | 1/16 (6.3%) | |
| Gait disturbance | 1/16 (6.3%) | |
| Infections and infestations | ||
| Rash pustular | 1/16 (6.3%) | |
| Investigations | ||
| Aspartate aminotransferase increased | 3/16 (18.8%) | |
| Platelet count decreased | 3/16 (18.8%) | |
| Alanine aminotransferase increased | 2/16 (12.5%) | |
| Alkaline phosphatase increased | 1/16 (6.3%) | |
| Blood bilirubin increased | 1/16 (6.3%) | |
| Metabolism and nutrition disorders | ||
| Hyperglycemia | 3/16 (18.8%) | |
| Anorexia | 2/16 (12.5%) | |
| Hyponatremia | 2/16 (12.5%) | |
| Hypoalbuminemia | 1/16 (6.3%) | |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 1/16 (6.3%) | |
| Nervous system disorders | ||
| Dizziness | 1/16 (6.3%) | |
| Tremor | 2/16 (12.5%) | |
| Ataxia | 1/16 (6.3%) | |
| Nervous system disorders - Other, specify | 1/16 (6.3%) | |
| Peripheral motor neuropathy | 1/16 (6.3%) | |
| Peripheral sensory neuropathy | 1/16 (6.3%) | |
| Syncope | 1/16 (6.3%) | |
| Psychiatric disorders | ||
| Insomnia | 1/16 (6.3%) | |
| Renal and urinary disorders | ||
| Urinary frequency | 1/16 (6.3%) | |
| Respiratory, thoracic and mediastinal disorders | ||
| Nasal congestion | 1/16 (6.3%) | |
| Sore throat | 1/16 (6.3%) | |
| Skin and subcutaneous tissue disorders | ||
| Dry skin | 5/16 (31.3%) | |
| Pruritus | 5/16 (31.3%) | |
| Rash maculo-papular | 4/16 (25%) | |
| Rash acneiform | 1/16 (6.3%) | |
| Vascular disorders | ||
| Hot flashes | 1/16 (6.3%) | |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Neil Segal, MD, PhD |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 646-888-4187 |
| segaln@mskcc.org |
- 14-109