RITUXIMAB + IMMUNOTHERAPY IN FOLLICULAR LYMPHOMA

• ClinicalTrials.gov Identifier: NCT03636503
• Recruitment Status: Active, not recruiting
• First Posted: August 17, 2018
• Last Update Posted: March 18, 2022
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Pfizer
• Information provided by (Responsible Party): Caron A. Jacobson, Dana-Farber Cancer Institute

Study Description

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

Condition or disease	Intervention/treatment	Phase
Follicular Lymphoma	Drug: Rituximab; Drug: Utomilumab; Drug: Avelumab; Drug: PF04518600	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Cohort Phase 1b Clinical Trial of Rituximab in Combination With Immunotherapy in Untreated and Previously Treated Follicular Lymphoma
• Actual Study Start Date: October 30, 2018
• Actual Primary Completion Date: July 23, 2021
• Estimated Study Completion Date: October 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rituximab +Utomilumab+Avelumab; 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	Drug: Rituximab; Rituximab works by targeting the CD20 antigen on normal and malignant B-cells. Then the body's natural immune defenses are recruited to attack and kill the marked B-cells. Stem cells (young cells in the bone marrow that will develop into the various types of cells) do not have the CD20 antigen. This allows healthy B-cells to regenerate after treatmen; Drug: Utomilumab; Utomilumab is a drug which may stimulate the immune system against tumor cells. Because it activate the immune system, it is sometimes called immunotherapy drug; Drug: Avelumab; Avelumab is a drug which may stimulate the immune system against tumor cells. Because it activate the immune system, it is sometimes called immunotherapy drug
Experimental: Rituximab+Utomilumab+PF04518600; 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	Drug: Rituximab; Rituximab works by targeting the CD20 antigen on normal and malignant B-cells. Then the body's natural immune defenses are recruited to attack and kill the marked B-cells. Stem cells (young cells in the bone marrow that will develop into the various types of cells) do not have the CD20 antigen. This allows healthy B-cells to regenerate after treatmen; Drug: Utomilumab; Utomilumab is a drug which may stimulate the immune system against tumor cells. Because it activate the immune system, it is sometimes called immunotherapy drug; Drug: PF04518600; In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40
Experimental: Rituximab+Avelumab+PF04518600; Rituximab is administered intravenously per institutional standards for four weekly treatments for cycle 1 only; Avelumab is administered intravenously over 1 hour once every 2 weeks; PF-04518600 is administered intravenously over 1 hour on day 1 and day 15	Drug: Rituximab; Rituximab works by targeting the CD20 antigen on normal and malignant B-cells. Then the body's natural immune defenses are recruited to attack and kill the marked B-cells. Stem cells (young cells in the bone marrow that will develop into the various types of cells) do not have the CD20 antigen. This allows healthy B-cells to regenerate after treatmen; Drug: Avelumab; Avelumab is a drug which may stimulate the immune system against tumor cells. Because it activate the immune system, it is sometimes called immunotherapy drug; Drug: PF04518600; In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40

Outcome Measures

Primary Outcome Measures :

1. Recommended phase 2 dosing [ Time Frame: 2 years ]
2. Complete response rate [ Time Frame: 2 years ]
   Lugano criteria

Secondary Outcome Measures :

1. Partial Response Rate [ Time Frame: 2 years ]
   Lugano criteria
2. Objective response rate [ Time Frame: 2 years ]
   Lugano criteria
3. Objective response rate [ Time Frame: 2 years ]
   Lyric criteria
4. Stable disease rate [ Time Frame: 2 years ]
   Lugano criteria
5. Stable disease rate [ Time Frame: 2 years ]
   Lyric criteria
6. Progressive disease rate [ Time Frame: 2 years ]
   Lyric criteria
7. Progressive disease rate [ Time Frame: 2 years ]
   Lugano criteria
8. Complete response rate [ Time Frame: 2 years ]
   Lyric criteria
9. Progression FreeSurvival [ Time Frame: 2 years ]
   Lugano criteria
10. Progression FreeSurvival [ Time Frame: 2 years ]
    Lyric criteria
11. Overall Survival Rate [ Time Frame: 2 years ]
12. Time to Next Treatment Response Duration [ Time Frame: 2 years ]
13. Rate of Grade 3 and higher toxicities [ Time Frame: 2 years ]
    Regardless of attribution
14. Rate of Grade 3 and higher toxicities [ Time Frame: 2 years ]
    Related to study treatment
15. Rate of Grade 2 or higher toxicity [ Time Frame: 2 years ]
    Related to study treatment
16. Rate of Adverse events leading to discontinuation due to toxicity [ Time Frame: 2 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

  • Risk of local compressive symptoms
  • Splenomegaly (craniocaudal diameter > 16cm on CT imaging)
  • Clinically significant pleural or peritoneal effusion
  • Leukemic phase (>5x109/L circulating malignant cells)
  • Rapid generalized disease progression
  • Renal infiltration
  • Bone lesions
• Patients may have had a prior autologous stem cell transplant and may have been treated with autologous chimeric antigen receptor T-cells (CAR T-cells).
• Not in need of urgent cytoreductive therapy in the opinion of the investigator
• Measurable disease that has not been previously irradiated on CT scans of at least 1.5 cm, OR if the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation. Imaging must be completed no greater than 6 weeks prior to study enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A)

• Adequate hematologic and organ function:

  • Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by lymphoma in which case ANC must be >0.5x109/L
  • Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in which case platelets must be >50 x109/L
  • Creatinine < 1.5 x ULN (upper limit of normal) or estimated GFR > 40ml/min
  • Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case direct bilirubin must be < 3 x ULN
• AST/ALT < 2.5 X ULN, unless documented liver involvement by lymphoma, in which case AST/ALT must be <5 x ULN
• Age >18 years
• Ability to understand and the willingness to sign a written informed consent document.
• Willingness to provide pre-treatment (or recent archival w/o intervening therapy), and on-treatment tumor samples by core needle or excisional surgical biopsy

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.
• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least three years. Patients with prostate cancer are allowed if PSA is less than 1.
• Patients should not have received immunization with attenuated live vaccine within one week of study entry or during study period.
• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Women of child bearing potential (WOCBP) or male study participants of reproductive potential must agree to use double barrier birth control method of contraception during the course of the study treatment period and for 3 months after completing study treatment. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who are not postmenopausal (no menses) for at least 12 consecutive months. WOCBP must have a negative urine or serum pregnancy test within 14 days prior to administration of treatment.
• History of noncompliance to medical regimens.

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

  • New York Heart Association Class III or IV cardiac disease, including pre-existing clinically significant arrhythmia, congestive heart failure, or cardiomyopathy
  • Patients with a history of previous anthracycline treatment and are at risk of cardiac failure (New York Heart Association Class II or above) are excluded from cohorts A2, A3, and B2 (cohorts that include PF04518600)
  • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• Patients with any one of the following currently on or in the previous 6 months will be excluded from cohorts A2, A3, and B2 (any cohort that includes treatment with PF04518600) myocardial infarction, congenital long QT syndrome, torsade's de points, left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism or other clinically significant episode of thrombo-embolic disease*. Ongoing cardiac dysrhythmias of NCI CTCAE grade > 2, atrial fibrillation of any grade, or QTcF interval >470msec at screening (except in case of right bundle branch block, these cases must be discussed with the principal investigator). *Cases must be discussed in detail with the principal investigator to judge eligibility. Anticoagulation (heparin only, no vitamin K antagonists or factor Xa inhibitors will be allowed if indicated.
• Other uncontrolled intercurrent illness that would limit adherence to study requirements

Contacts and Locations

Locations

United States, California

City of Hope

Duarte, California, United States, 91010

United States, Connecticut

Yale New-Haven Hospital

New Haven, Connecticut, United States, 06510

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Missouri

Washington University in St. Louis

Saint Louis, Missouri, United States, 63130

Sponsors and Collaborators

Dana-Farber Cancer Institute

Pfizer

Investigators

• Principal Investigator: Caron A. Jacobson, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Caron A. Jacobson, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03636503
• Other Study ID Numbers: 18-311
• First Posted: August 17, 2018
• Last Update Posted: March 18, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Caron A. Jacobson, Dana-Farber Cancer Institute:

Lymphoma

Additional relevant MeSH terms:

Lymphoma; Lymphoma, Follicular; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Rituximab; Avelumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents