Rituximab + Immunotherapy in Follicular Lymphoma

A Multi-Cohort Phase 1b Clinical Trial of Rituximab in Combination With Immunotherapy in Untreated and Previously Treated Follicular Lymphoma

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03636503

Enrollment

Registered

2018-08-17

Start date

2018-10-30

Completion date

2023-07-30

Last updated

2025-02-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Follicular Lymphoma

Keywords

Lymphoma

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.

Interventions

DRUGRituximab

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 treatment

DRUGUtomilumab

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

DRUGAvelumab

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

DRUGPF04518600

In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Recommended Phase 2 Dosing	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	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

Measure	Time frame	Description
Number of Participants With Objective Response Per LYRIC Criteria	Response assessed after completing treatment (6 months)	Objective response rate is defined as complete + partial response (CR + PR) Per LYRIC criteria, CR 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 Per LYRIC criteria, PR is defined as PET-CT Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. Or On CT ≥ 50% decrease in SPD of up to 6 target measurable nodes and extranodal sites; no increase in non-measured lesions; spleen if enlarged must have regressed by \>50% in length beyond normal
Number of Participants With Complete Response Per LYRIC Criteria	Response assessed after completing treatment (6 months)	Per LYRIC criteria, 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
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	Time from registration until earlier of progression (Lugano criteria) or death from any cause, censored at date last known alive and progression-free
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	Time from registration until earlier of progression (LYRIC criteria) or death from any cause, censored at date last known alive and progression-free
Number of Participants With Partial Response Per Lugano Criteria	Response assessed after completing treatment (6 months)	Per 2014 Lugano criteria, partial response is defined as PET-CT Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size Or On CT ≥ 50% decrease in SPD of up to 6 target measurable nodes and extranodal sites; no increase in non-measured lesions; spleen if enlarged must have regressed by \>50% in length beyond normal
Number of Participants With Grade 3 and Higher Toxicities	6 cycles (approximately 6 months) of treatment	Number of patients who experience any adverse event with grade 3 or higher regardless of attribution to one or more study treatments
Number of Participants With Grade 3 and Higher Related Toxicities	6 cycles (approximately 6 months) of treatment	Number of patients who experience any adverse event with grade 3 or higher related to one or more study treatments
Number of Participants With Grade 2 or Higher Toxicity	6 cycles (approximately 6 months) of treatment followed	Number of patients who experience any adverse event with grade 2 or higher regardless of treatment attribution
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	Time from registration until death from any cause, censored at date last known alive
Number of Participants With Objective Response Per Lugano Criteria	Response assessed after completing treatment (6 months)	Objective response rate is defined as complete + partial response (CR + PR) Per 2014 Lugano criteria, CR 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 Per 2014 Lugano criteria, PR is defined as PET-CT Score 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size. Or On CT ≥ 50% decrease in SPD of up to 6 target measurable nodes and extranodal sites; no increase in non-measured lesions; spleen if enlarged must have regressed by \>50% in length beyond normal

Countries

United States

Participant flow

Pre-assignment details

The study was terminated early due to the drug manufacturer stopping drug supply.

Participants by arm

Arm	Count
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 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 treatment 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 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	5
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 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 treatment 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 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 -PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg	4
PF04518600-0.3mg PF04518600: In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40	3
Rituximab+PF04518600-0.3mg * Rituximab is administered intravenously per institutional standards * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg 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 treatment PF04518600: In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40	3
Rituximab+Utomilumab+PF04518600-0.3mg * Rituximab is administered intravenously per institutional standards * Utomilumab is administered intravenously over 1 hour once every * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg 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 treatment 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 PF04518600: In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40	9
Rituximab+PF04518600-0.3mg+Avelumab-3mg * 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, 3mg/kg * PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg 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 treatment PF04518600: In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40 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	0
Rituximab+PF04518600-0.3mg+Avelumab-10mg * 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 * Avelumab is administered intravenously over 1 hour once every 2 weeks, 10mg/kg 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 treatment PF04518600: In the presence of tumor-associated antigens (TAAs), this may promote a T-cell-mediated immune response against TAA-expressing tumor cells. OX40 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	0
Total	24

Baseline characteristics

Characteristic	Rituximab+Utomilumab+Avelumab-10mg	PF04518600-0.3mg	Rituximab+PF04518600-0.3mg	Rituximab+Utomilumab+PF04518600-0.3mg	Rituximab+PF04518600-0.3mg+Avelumab-3mg	Rituximab+Utomilumab+Avelumab-3mg	Rituximab+PF04518600-0.3mg+Avelumab-10mg	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	2 Participants	1 Participants	2 Participants	2 Participants	0 Participants	0 Participants	0 Participants	7 Participants
Age, Categorical Between 18 and 65 years	2 Participants	2 Participants	1 Participants	7 Participants	0 Participants	5 Participants	0 Participants	17 Participants
Age, Continuous	61 years	58 years	65 years	57 years	—	58 years	—	58 years
ECOG Performance Status 0 - Fully active, able to carry on all pre-disease performance without restriction	2 Participants	1 Participants	2 Participants	6 Participants	0 Participants	1 Participants	0 Participants	12 Participants
ECOG Performance Status 1 - Restricted in physically strenuous activity but able to carry out light or sedentary work	2 Participants	2 Participants	1 Participants	3 Participants	0 Participants	4 Participants	0 Participants	12 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	3 Participants	3 Participants	8 Participants	0 Participants	5 Participants	0 Participants	23 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	0 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	4 Participants	3 Participants	2 Participants	8 Participants	0 Participants	5 Participants	0 Participants	22 Participants
Region of Enrollment United States	4 Participants	3 Participants	3 Participants	9 Participants	0 Participants	5 Participants	0 Participants	24 Participants
Sex: Female, Male Female	2 Participants	0 Participants	2 Participants	2 Participants	0 Participants	0 Participants	0 Participants	6 Participants
Sex: Female, Male Male	2 Participants	3 Participants	1 Participants	7 Participants	0 Participants	5 Participants	0 Participants	18 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk
deaths Total, all-cause mortality	2 / 6	1 / 4	0 / 3	0 / 3	0 / 9	0 / 0	0 / 0
other Total, other adverse events	4 / 6	3 / 4	2 / 3	3 / 3	6 / 9	0 / 0	0 / 0
serious Total, serious adverse events	4 / 6	0 / 4	0 / 3	1 / 3	1 / 9	0 / 0	0 / 0

Outcome results

Primary

Number of Participants With Complete Response Per Lugano Criteria

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

Time frame: Response assessed after completing treatment (6 months)