Clinical trial NCT02335918: A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors
Official title: A Phase l/ll Dose Escalation and Cohort Expansion Study of the Safety, Tolerability and Efficacy of Anti-CD27 Antibody (Varlilumab) Administered in Combination With Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Ovarian Carcinoma-Enrollment Completed
Colorectal Cancer (CRC)-Enrollment Completed
Renal Cell Carcinoma (RCC) (Phase ll Only)
Glioblastoma (GBM) (Phase ll Only)-Enrollment Completed
Keywords: Opdivo®
Lead sponsor: Celldex Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Bristol-Myers Squibb
First posted: 2015-01-12
Enrollment: 175
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a study to determine the clinical benefit (how well the drug works), safety, and tolerability of combining varlilumab and nivolumab (also known as Opdivo® , BMS-936558). Both drugs target the immune system and may act to promote anti-cancer effects.

Detailed description: Varlilumab is a fully human monoclonal antibody that binds to a molecule called CD27 found on certain immune cells and may act to promote anti-tumor effects.

Nivolumab is a fully human monoclonal antibody that binds to a molecule called PD-1 on immune cells and promotes anti-tumor effects.

Eligible patients that enroll in the dose escalation portion of the study will be assigned to one of three dose levels of varlilumab in combination with 3 mg/kg of nivolumab. The first phase of the study will test the safety profile of the combination and determine which dose will be studied in Phase ll of the overall study.

During Phase ll, depending on cancer type, groups of patients will be enrolled and receive varlilumab at a dose of either 3 mg/kg every 2 weeks, 3 mg/kg every 12 weeks, or 0.3 mg/kg every 4 weeks in combination with nivolumab at 240 mg.

All patients enrolled in the study will be closely monitored to determine if there is response to the treatment as well as for any side effects that may occur.

Eligibility criteria: Key Inclusion Criteria:

1. Histologically-diagnosed advanced (unresectable and/or metastatic) Non-small Cell Lung Cancer (Phase l only), Melanoma (Phase l only), Colorectal, Head and Neck SCC (squamous cell carcinoma), Ovarian Cancer, Glioblastoma or Renal Cell Carcinoma.

   * 1a. Head and Neck

   Stage III/IV squamous cell carcinoma; Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant, primary, recurrent or metastatic setting (or within 9 months if the patient received \> 1 platinum-based chemotherapy regimen in the metastatic setting). Active brain metastases or leptomeningeal metastases are excluded; nasopharyngeal cancer, confirmed recurrent or metastatic carcinoma of the nasopharynx and salivary gland or non-squamous histologies are also excluded.
   * 1b. Ovarian

   Recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal carcinoma requiring original or subsequent relapse histologic documentation. A platinum-taxane based chemotherapy regimen as frontline therapy must have been completed.

   Any histologic diagnosis of borderline, low malignant potential epithelial carcinoma are excluded.
   * 1c. Colorectal Cancer -Enrollment Completed

   Metastatic or recurrent; prior treatment progression during, after, or intolerant following the last administration of approved standard therapies (required therapies apply).
   * 1d. Glioblastoma -Enrollment Completed

   Have histologically confirmed World Health Organization Grade IV malignant glioma (glioblastoma).
   * Previous first line therapy with at least radiotherapy and temozolomide.
   * Participants must have shown unequivocal evidence of tumor progression.
   * More than one relapse, secondary glioblastoma and prior treatment with bevacizumab are excluded.

   An interval of at least 12 weeks from the completion of radiation therapy to start of study treatment is required.
   * 1e. Renal Cell Carcinoma

   Have histologically confirmed diagnosis of predominant clear cell renal cell carcinoma.
   * Must have received 1 or 2 prior anti-angiogenic therapies.
   * No more than 5 total previous regimens of systemic therapy, including cytokines and cytotoxic chemotherapy.
   * Disease progression during or after the last treatment regimen and within 6 months before study entry.
2. No more than 5 prior anticancer regimens for advanced (recurrent, locally advanced or metastatic) disease except for patients with GBM which must have first recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI).
3. Measurable (target) disease.
4. Life expectancy ≥ 12 weeks.
5. If of childbearing potential (male or female), agree to practice an effective form of contraception during study treatment and for at least 23 weeks after for female and 31 weeks after for male following last treatment dose.

Key Exclusion Criteria:

1. History of severe hypersensitivity reactions to other monoclonal antibodies.
2. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody.
3. Receipt of anti-CTLA-4 or anti-CD27 antibody within 3 months prior to the planned start of study treatment.
4. Use of any monoclonal based therapies within 2-4 weeks prior to the first dose of study treatment.
5. Chemotherapy within 21 days or at least 5 half-lives (whichever is shorter) prior to the planned start of study treatment.
6. BRAF/MEK inhibitors within 2 weeks prior to the first dose of study treatment.
7. Systemic radiation therapy within 4 weeks, prior focal radiotherapy within 2 weeks, or radiopharmaceuticals (strontium, samarium) within 8 weeks prior to the first dose of study treatment.
8. Use of immunosuppressive medications within 4 weeks or systemic corticosteroids within 2 weeks prior to first dose of study treatment.
9. Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or in situ cancers; or any other cancer from which the patient has been disease-free for at least 3 years.
10. Active, untreated central nervous system metastases.
11. Active autoimmune disease or a documented history of autoimmune disease
12. Active diverticulitis.
13. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
14. Significant cardiovascular disease

Primary outcomes:
measure: Phase I: Number of participants with treatment-related adverse events as determined by CTCAE v4.0, dose-limiting toxicities, and laboratory abnormalities.
timeFrame: Safety follow-up is 100 days from last study drug dose.
measure: Phase II: Preliminary antitumor activity of the combination of varlilumab and nivolumab as measured by objective response rate (ORR) in patients with CRC, ovarian cancer, RCC and SCCHN and Overall Survival-12 months in GBM.
timeFrame: Evaluated every 8 weeks following treatment initiation until treatment is discontinued or disease progression, for up to 3 years.
Secondary outcomes:
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Palo Alto
country: United States
facility: The Stanford Center for Clinical and Translational Education and Research
state: California
city: San Francisco
country: United States
facility: UCSF Helen Diller Family Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Medical Center
state: Colorado
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale University Cancer Center
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: George Washington University School of Medicine and Health Sciences
state: District of Columbia
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Marietta
country: United States
facility: Northwest Georgia Oncology Centers PC
state: Georgia
city: Fort Wayne
country: United States
facility: Parkview Research Center
state: Indiana
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Providence Health & Services
state: Oregon
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute Research
state: Virginia
Study officials:
References:
citation: Sanborn RE, Pishvaian MJ, Callahan MK, Weise A, Sikic BI, Rahma O, Cho DC, Rizvi NA, Sznol M, Lutzky J, Bauman JE, Bitting RL, Starodub A, Jimeno A, Reardon DA, Kaley T, Iwamoto F, Baehring JM, Subramaniam DS, Aragon-Ching JB, Hawthorne TR, Rawls T, Yellin M, Keler T. Safety, tolerability and efficacy of agonist anti-CD27 antibody (varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors. J Immunother Cancer. 2022 Aug;10(8):e005147. doi: 10.1136/jitc-2022-005147.