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Follicular LymphomaPhase 1NCT03636503

Rituximab + Immunotherapy in Follicular Lymphoma

A Phase 1 study testing Rituximab, Utomilumab and Avelumab in people with Follicular Lymphoma, run by Dana-Farber Cancer Institute at 6 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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 Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Follicular Lymphoma
What is being tested?
Rituximab, Utomilumab and Avelumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
6 sitesUnited States
Study dates
30 Oct 2018to 30 Jul 2023
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • Emory University

    Atlanta, Georgia, 30322

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • University of Chicago

    Chicago, Illinois, 60637

  • City of Hope

    Duarte, California, 91010

  • Yale New-Haven Hospital

    New Haven, Connecticut, 06510

  • Washington University in St. Louis

    St Louis, Missouri, 63130

Other trials in United States

About this study

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

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
Read the 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.

Being tested
Rituximab, Utomilumab, Avelumab, PF04518600
Keywords
Lymphoma
Medical subject headings
Lymphoma, Follicular, Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RituximabDrug

    Also called Rituxan

    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

  • UtomilumabDrug

    Also called PF-05082566, PF05082566

    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

  • AvelumabDrug

    Also called Bavencio

    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

  • PF04518600Drug

    Also called PF-04518600

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

Study groups in NCT03636503
Study groupRoleWhat they receive
Rituximab+Utomilumab+Avelumab-3mgExperimental* 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
Receives: Drug: Rituximab; Drug: Utomilumab; Drug: Avelumab
Rituximab+Utomilumab+Avelumab-10mgExperimental* 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
Receives: Drug: Rituximab; Drug: Utomilumab; Drug: Avelumab
PF04518600-0.3mgExperimental-PF-04518600 is administered intravenously over 1 hour on day 1 and day 15, 0.3mg/kg
Receives: Drug: PF04518600
Rituximab+PF04518600-0.3mgExperimental* 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
Receives: Drug: Rituximab; Drug: PF04518600
Rituximab+Utomilumab+PF04518600-0.3mgExperimental* 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
Receives: Drug: Rituximab; Drug: Utomilumab; Drug: PF04518600
Rituximab+PF04518600-0.3mg+Avelumab-3mgExperimental* 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
Receives: Drug: Rituximab; Drug: Avelumab; Drug: PF04518600
Rituximab+PF04518600-0.3mg+Avelumab-10mgExperimental* 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
Receives: Drug: Rituximab; Drug: Avelumab; Drug: PF04518600

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Recommended Phase 2 Dosing

    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.

    Measured: 6 months total, assessed after each 28-day cycle

  2. 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

    Measured: Response assessed after completing treatment (6 months)

Secondary outcomes (10)

  1. Number of Participants With Partial Response Per Lugano Criteria

    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

    Measured: Response assessed after completing treatment (6 months)

  2. Number of Participants With Objective Response Per Lugano Criteria

    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

    Measured: Response assessed after completing treatment (6 months)

  3. Number of Participants With Objective Response Per LYRIC Criteria

    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

    Measured: Response assessed after completing treatment (6 months)

  4. Number of Participants With Complete Response Per LYRIC Criteria

    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

    Measured: Response assessed after completing treatment (6 months)

  5. Progression-Free Survival Per Lugano Criteria

    Time from registration until earlier of progression (Lugano criteria) or death from any cause, censored at date last known alive and progression-free

    Measured: 6 cycles (approximately 6 months) of treatment followed by 24 months of active follow-up with contact every 3 months

  6. Progression-Free Survival Per LYRIC Criteria

    Time from registration until earlier of progression (LYRIC criteria) or death from any cause, censored at date last known alive and progression-free

    Measured: 6 cycles (approximately 6 months) of treatment followed by 24 months of active follow-up with contact every 3 months

  7. Overall Survival

    Time from registration until death from any cause, censored at date last known alive

    Measured: 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

  8. Number of Participants With Grade 3 and Higher Toxicities

    Number of patients who experience any adverse event with grade 3 or higher regardless of attribution to one or more study treatments

    Measured: 6 cycles (approximately 6 months) of treatment

  9. Number of Participants With Grade 3 and Higher Related Toxicities

    Number of patients who experience any adverse event with grade 3 or higher related to one or more study treatments

    Measured: 6 cycles (approximately 6 months) of treatment

  10. Number of Participants With Grade 2 or Higher Toxicity

    Number of patients who experience any adverse event with grade 2 or higher regardless of treatment attribution

    Measured: 6 cycles (approximately 6 months) of treatment followed

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Aug 2018
  2. Study start30 Oct 2018
  3. Primary completion23 Jul 2021
  4. Study completion30 Jul 2023

Why it stopped: Stopped was stopped prematurely due to drug manufacturer withdrawing supply/funding. Patients already enrolled on study were allowed to continue treatment.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03636503
Sponsor's protocol ID
18-311
Status last verified
Jan 2025
First submitted
2 Aug 2018
Last updated
6 Feb 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Merryman RW, Redd RA, Freedman AS, Ahn IE, Brown JR, Crombie JL, Davids MS, Fisher DC, Jacobsen ED, Kim AI, LaCasce AS, Ng S, Odejide OO, Parry EM, Isufi I, Kline J, Cohen JB, Mehta-Shah N, Bartlett NL, Mei M, Kuntz TM, Wolff J, Rodig SJ, Armand P, Jacobson CA. A multi-cohort phase 1b trial of rituximab in combination with immunotherapy doublets in relapsed/refractory follicular lymphoma. Ann Hematol. 2024 Jan;103(1):185-198. doi: 10.1007/s00277-023-05475-0. Epub 2023 Oct 18.

    PubMed 37851072

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Rituximab, Utomilumab and Avelumab in people with Follicular Lymphoma, run by Dana-Farber Cancer Institute at 6 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 6 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 Feb 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recommended Phase 2 Dosing (time frame: 6 months total, assessed after each 28-day cycle). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03636503, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2025.

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