A Multi-Cohort Phase 1b Clinical Trial of Rituximab in Combination With Immunotherapy in Untreated and Previously Treated Follicular Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Rituximab
- Conditions
- Follicular Lymphoma
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 24
- Locations
- 6
- Primary Endpoint
- Recommended Phase 2 Dosing
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This research study is studying several new investigational drug combinations as a possible treatment for follicular lymphoma.
The drugs involved are:
- Rituximab
- Utomilumab
- Avelumab
- PF-04518600
Detailed Description
This research study is a Phase 1 clinical trial. Phase 1 clinical trials test the safety of an investigational intervention and also try to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied. Utomilumab and avelumab are drugs which may stimulate the immune system against tumor cells. Because they activate the immune system, they are sometimes called immunotherapy drugs. The FDA (the U.S. Food and Drug Administration) has not approved utomilumab or avelumab for treatment of this cancer. Rituximab is approved by the FDA (the U.S. Food and Drug Administration) as a treatment option for this disease. The purpose of this research is to learn about the effects of combining the immunotherapy drugs utomilumab and avelumab with rituximab in follicular lymphoma. The investigators hope to learn how safe the combinations of treatments are for participants with follicular lymphoma.
Investigators
Caron A. Jacobson, MD
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically determined follicular lymphoma, grade 1-3A, with pathologic review at the participating institutions, that has either:
- •Relapsed or primary refractory after at least one line of therapy including anti-CD-20 monoclonal antibody treatment (part A) or;
- •Has had no previous anti-lymphoma therapy other than corticosteroids or radiotherapy (part B).
- •Patients with active histologic transformation are excluded. Relapsed/refractory patients with prior transformation may be included as long as there is no evidence of transformation at the time of study entry by pathology, imaging, or clinical status
- •Patients in part B, without prior anti-lymphoma therapy, must be in need of treatment as defined by any of the following criteria:
- •Symptomatic adenopathy
- •Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC \<1.5x109/L; absolute neutrophil count \[ANC\] \<1.0x109/L, Hgb \<10g/dL; platelets \<100x109/L)
- •Constitutional symptoms
- •Maximum diameter of disease \> 7cm
- •-\>3 nodal sites of involvement
Exclusion Criteria
- •Patients currently receiving anticancer therapies or who have received anticancer therapies within 28 days of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.), or 56 days for radioimmunotherapy. Steroids for symptom palliation are allowed, but must be either discontinued or on stable doses of \< 10mg daily of prednisone (or the equivalent) at the time of initiation of protocol therapy.
- •Patients may not be receiving any other investigational agents, or have received investigational agents within 4 weeks (or 3 half-lives, whichever is longer) of beginning treatment.
- •History of severe allergic or anaphylactic reactions to monoclonal antibody therapy unless in consultation with an allergy specialist they are deemed eligible for retreatment with desensitization.
- •Patients who have previously received therapy with any drug that works by a similar mechanism of action as any drug being tested in a given cohort will be excluded from that cohort but will be allowed to enroll in other open cohorts.
- •Patients who have undergone prior allogeneic stem cell transplantation
- •Patients with a history of or active autoimmune disease (except controlled asthma, Hashimoto thyroiditis, atopic dermatitis, and/or vitiligo), or requiring systemic corticosteroids at a dose of 10mg prednisone equivalent daily. Patients with a history of autoimmune disease who never required corticosteroids and with no evidence of disease activity, and in whom the risk of reactivation is felt not to be serious, may be enrolled after discussion with the overall study chair. Exceptions to this are patients with a history of inflammatory bowel disease (ulcerative colitis and Crohn's disease). These patients are excluded regardless of whether their disease is active or inactive.
- •Patients with active pneumonitis or colitis, or patients with chronic liver disease and/or cirrhosis
- •Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study.
- •Patients with known leptomeningeal or brain metastases. Imaging or spinal fluid analysis to exclude CNS involvement is not required, unless there is clinical suspicion by the treating investigator.
- •Patients with known HIV infection or hepatitis B or C infection. Testing for HIV is optional. Testing for hepatitis B and C is mandatory. Patients with hepatitis B core Ab positivity but negative surface antigen and negative viral load may be enrolled if they can be treated with a prophylactic agent (eg, entecavir); patients with hepatitis C seropositivity who have undergone successful treatment with negative viral load can also be enrolled.
Arms & Interventions
Rituximab+Utomilumab+Avelumab-3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg
Intervention: Rituximab
Rituximab+Utomilumab+Avelumab-3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg
Intervention: Utomilumab
Rituximab+Utomilumab+Avelumab-3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg
Intervention: Avelumab
Rituximab+Utomilumab+Avelumab-10mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Intervention: Rituximab
Rituximab+Utomilumab+Avelumab-10mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Intervention: Utomilumab
Rituximab+Utomilumab+Avelumab-10mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Intervention: Avelumab
PF04518600-0.3mg
-PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Intervention: PF04518600
Rituximab+PF04518600-0.3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Intervention: Rituximab
Rituximab+PF04518600-0.3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Intervention: PF04518600
Rituximab+Utomilumab+PF04518600-0.3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Intervention: Rituximab
Rituximab+Utomilumab+PF04518600-0.3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Intervention: Utomilumab
Rituximab+Utomilumab+PF04518600-0.3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Intervention: PF04518600
Rituximab+PF04518600-0.3mg+Avelumab-3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg
Intervention: Rituximab
Rituximab+PF04518600-0.3mg+Avelumab-3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg
Intervention: Avelumab
Rituximab+PF04518600-0.3mg+Avelumab-3mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 3mg/kg
Intervention: PF04518600
Rituximab+PF04518600-0.3mg+Avelumab-10mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Intervention: Rituximab
Rituximab+PF04518600-0.3mg+Avelumab-10mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Intervention: Avelumab
Rituximab+PF04518600-0.3mg+Avelumab-10mg
* Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only * Utomilumab is administered intravenously over 1 hour once every 4 weeks * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg
Intervention: PF04518600
Outcomes
Primary Outcomes
Recommended Phase 2 Dosing
Time Frame: 6 months total, assessed after each 28-day cycle
Patients assessed for DLT after each 28-day cycle of treatment. Up to two cohorts of 3 patients per dose level plus expansion cohort. Rituximab/Utomilumab/Avelumab arm assessed 2 dose levels. Rituximab/Utomilumab/PF04518600 assessed 3 dose levels. Rituximab/PF04518600/Avelumab assessed 2 dose levels.
Number of Participants With Complete Response Per Lugano Criteria
Time Frame: Response assessed after completing treatment (6 months)
Per 2014 Lugano criteria, a complete response is defined as PET-CT, score 1, 2, or 3\* with or without a residual mass on 5PS Or on CT, target nodes/nodal masses must regress to ≤ 1.5 cm in LDi, and no extralymphatic sites of disease
Secondary Outcomes
- Number of Participants With Partial Response Per Lugano Criteria(Response assessed after completing treatment (6 months))
- Number of Participants With Objective Response Per Lugano Criteria(Response assessed after completing treatment (6 months))
- Number of Participants With Objective Response Per LYRIC Criteria(Response assessed after completing treatment (6 months))
- Number of Participants With Complete Response Per LYRIC Criteria(Response assessed after completing treatment (6 months))
- Progression-Free Survival Per Lugano Criteria(6 cycles (approximately 6 months) of treatment followed by 24 months of active follow-up with contact every 3 months)
- Progression-Free Survival Per LYRIC Criteria(6 cycles (approximately 6 months) of treatment followed by 24 months of active follow-up with contact every 3 months)
- Overall Survival(6 cycles (approximately 6 months) of treatment followed by 24 months of active follow-up with contact every 3 months followed by 3-year survival follow-up with contact every 6 months)
- Number of Participants With Grade 3 and Higher Toxicities(6 cycles (approximately 6 months) of treatment)
- Number of Participants With Grade 3 and Higher Related Toxicities(6 cycles (approximately 6 months) of treatment)
- Number of Participants With Grade 2 or Higher Toxicity(6 cycles (approximately 6 months) of treatment followed)