Rituximab in Combination with Immunotherapy in Treating Patients with Grade 1-3A Recurrent and Refractory Follicular Lymphoma

Status: Active

Description

This phase Ib trial studies the best dose of immunotherapy combinations with rituximab in treating patients with grade 1-3A follicular lymphoma that has come back or does not respond to treatment. Immunotherapy with rituximab, utomilumab, and PF-04518600 may induce changes in body’s immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving rituximab in combination with immunotherapy may work better in treating patients with follicular lymphoma.

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) * 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 (white blood cells [WBC] < 1.5x10^9/L; absolute neutrophil count [ANC] < 1.0x10^9/L, hemoglobin [Hgb] < 10g/dL; platelets < 100x10^9/L) * Constitutional symptoms * Maximum diameter of disease >= 7 cm * >= 3 nodal sites of involvement * Risk of local compressive symptoms * Splenomegaly (craniocaudal diameter >= 16 cm on computed tomography [CT] imaging) * Clinically significant pleural or peritoneal effusion * Leukemic phase (> 5x10^9/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
  • Absolute neutrophil count >= 1.0 x 10^9/L unless due to marrow involvement by lymphoma in which case ANC must be > 0.5 x 10^9/L
  • Platelets > 75 x10^9/L, unless due to marrow involvement by lymphoma, in which case platelets must be > 50 x10^9/L
  • Creatinine < 1.5 x ULN (upper limit of normal) or estimated glomerular filtration rate (GFR) > 40ml/min
  • Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case direct bilirubin must be < 3 x ULN
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 2.5 X ULN, unless documented liver involvement by lymphoma, in which case AST/ALT must be < 5 x ULN
  • 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 central nervous system (CNS) involvement is not required, unless there is clinical suspicion by the treating investigator
  • Patients with known human immunodeficiency virus (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 antibody (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 prostate specific antigen (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 preexisting 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 PF-04518600) * 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 PF-04518600) 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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2, atrial fibrillation of any grade, or corrected QT using Fridericia's formula (QTcF) interval > 470 msec 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

Locations & Contacts

Illinois

Chicago
University of Chicago Comprehensive Cancer Center
Status: Active
Contact: Justin Paul Kline
Email: Jkline@medicine.bsd.uchicago.edu

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Caron Alyce Jacobson
Phone: 617-632-5847
Email: cajacobson@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: Caron Alyce Jacobson
Phone: 617-632-5847
Email: cajacobson@partners.org

Missouri

Saint Louis
Washington University School of Medicine
Status: Active
Contact: Neha Mehta-Shah
Email: Mehta-n@wustl.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dosing (RP2D) of immunotherapy combinations with rituximab for the treatment of relapsed/refractory or untreated follicular lymphoma.

II. To evaluate clinical efficacy of immunotherapy in combination with rituximab in relapsed/refractory or untreated follicular lymphoma (FL) as measured by the complete response (CR) rate using the 2014 Lugano criteria.

SECONDARY OBJECTIVES:

I. To evaluate clinical efficacy of immunotherapy in combination with rituximab in relapsed/refractory or untreated FL as measured by: objective response rate (2014 Lugano); overall and complete response rate (Lymphoma Response to Immunomodulatory therapy Criteria [LyRIC]); progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT); objective response rate, complete response rate, and minimal residual disease (MRD) negativity will be stratified by grade (1-2 versus 3A) and by FL International Prognostic Index (FLIPI).

II. Evaluate safety of these combinations in relapsed/refractory FL and previously untreated FL.

EXPLORATORY OBJECTIVES:

I. To perform correlative laboratory studies using pre-treatment and on-treatment peripheral blood and tumor samples to evaluate for biomarkers of response and resistance.

II. To analyze pre-treatment fecal microbiome to investigate relationship with response or resistance to immunotherapy.

III. Rate of MRD negativity at 6 and 12 months.

OUTLINE: This is a dose-escalation study of avelumab. Patients are assigned to 1 of 5 cohorts.

COHORT A1a, A1b and B1: Patients receive rituximab intravenously (IV) on days -6, 1, 8, and 15 of course 1. Patients also receive utomilumab IV over 1 hour on day 2 of course 1 and day 1 of subsequent courses, and avelumab IV over 1 hour on day 16 of course 1 and days 1 and 15 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

COHORT A2a Dose level 0: Patients receive anti-OX40 antibody PF-04518600 IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

COHORT A2a Dose Level 1: Patients receive rituximab IV on days -6, 1, 8, and 15 of course 1. Patients also receive anti-OX40 antibody PF-04518600 IV over 1 hour on days 2 and 15. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

COHORT A2a Dose level 2, A2b and B2: Patients receive rituximab IV on days -6, 1, 8, and 15 of course 1. Patients also receive utomilumab IV over 1 hour on day 2 of course 1 and day 2 of subsequent courses, and anti-OX40 antibody PF-04518600 IV over 1 hour on day 16 of course 1 and days 1 and 15 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

COHORT A3a and A3b: Patients receive rituximab IV on days -6, 1, 8, and 15 of course 1. Patients also receive anti-OX40 antibody PF-04518600 IV over 1 hour on days 2 and 15 of course 1 and days 1 and 15 of subsequent courses, and avelumab IV over 1 hour on day 16 of course 1 and days 1 and 15 of subsequent courses. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 24 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Caron Alyce Jacobson

Trial IDs

Primary ID 18-311
Secondary IDs NCI-2018-02767
Clinicaltrials.gov ID NCT03636503