Ublituximab Followed by Response-driven Addition of Umbralisib for Treatment-naive Follicular or Marginal Zone Lymphoma

March 19, 2024 updated by: University of Colorado, Denver

Ublituximab as Initial Therapy for Treatment-naive Follicular or Marginal Zone Lymphoma With Response-driven Addition of Umbralisib for Suboptimal Response

This is an open-label, Phase II interventional study in order to assess efficacy and safety of single agent ublituximab as initial therapy for FL (Follicular lymphoma) and MZL (Marginal zone lymphoma ) with response driven addition of umbralisib for suboptimal response.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Based on overall reporting in low tumor burden FL and MZL, CR rate of at least 30% was achieved when single agent rituximab was used in these subsets. The investigators assume that by administering ublituximab (both as a single agent and in combination with umbralisib for individuals who fail to achieve a CR [Complete response] with the single agent), the CR rate will increase to 50%. Efficacy will be assessed using the proportion of patients treated with ublituximab alone or with ublituximab administered in combination who have a complete response. Thus, the investigators will test the efficacy of ublituximab using a difference in proportions design by comparing an expected study population control rate of 50% to the comparison proportion being determined by the historical control CR rate of 30%. In other words, the null hypothesis is that the true response rate is 30%, and it will be formally tested against a one-sided alternative that the response rate is 50%.

Study Type

Interventional

Enrollment (Actual)

4

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Disease Related

  1. Subjects with histologically documented Follicular lymphoma CD20+ (Grade 1, 2 or 3a) OR Marginal zone lymphoma CD20+ (nodal, extranodal or splenic) according to World Health Organization (WHO) criteria.
  2. Ann Arbor Stage II (Non-contiguous), III or IV disease
  3. Patients must have a whole body or limited whole body PET/CT scan performed within 42 days prior to registration. CT portion of PET/CT will be done with contrast based on current NCCN guidelines unless patient has borderline renal function or allergic to contrast dye.
  4. Patients must have bone marrow biopsy performed within 6 months prior to registration
  5. Measurable node must have an LDi greater than 1.5 cms. In the absence of nodal lesions, measurable extranodal disease should have an LDi greated than 1 cm. In patients with Splenic Marginal Zone lymphoma, in the absence of nodal lesions, spleen size should should be over 14 cms with evidence of lymphoma in the bone marrow biopsy.
  6. For low tumor burden lymphomas (as determined by GELF criteria) : Include patients diagnosed within 2 years of diagnosis. Low tumor burden patients diagnosed more than 2 years from study entry will be allowed provided patients have documented progression.

Prior Therapy Criteria

1. Patients must be untreated advanced stage disease (Stage III or Stage IV) or Stage II (noncontiguous). (Exception: Involved field or involved site radiation given for localized diagnosis is not considered a line of therapy).

Clinical/Laboratory Criteria

  1. Patients must be ≥ 18 years of age and be able to swallow and retain oral medication
  2. ECOG performance status of 0-2
  3. Patients must have adequate bone marrow function as evidenced by ANC ≥ 1000/µL and platelets ≥ 50,000µL and Hb >= 8g/dl within 28 days prior to registration unsupported by growth factors.
  4. Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min

  5. Patients must have adequate hepatic function obtained within 28 days prior to registration and documented by all of the following:

    • Total bilirubin ≤ 1.5 x IULN (≤ 5 x IULN if secondary to lymphoma, Gilbert's syndrome, or medication related)
    • Direct bilirubin ≤ 1.5 x IULN (≤ 5 x IULN if secondary to lymphoma)
    • AST and ALT ≤ 2.5 x IULN (≤ 5 x IULN secondary to lymphoma)
  6. Patients must be willing to receive Pneumocystis jirovecii prophylaxis with sulfamethoxazole/trimethoprim, dapsone, and atovaquone or inhaled pentamadine, if they initiate combination umbralisib plus ublituximab (not for single agent ublituximab)
  7. Patients must have a complete history and physical examination within 28 days prior to registration

  8. Patients with follicular lymphoma must have the following components of Follicular Lymphoma International Prognostic Index (FLIPI) available from diagnosis, and collected again at time of registration:

    • Age
    • LDH
    • Number of nodal groups involved
    • Serum or plasma hemoglobin
    • Ann Arbor Stage Additionally, patients must have beta2-microglobulin collected at time of registration and response assessment.
  9. Female subjects of reproductive potential must have a negative serum pregnancy test within 3 days prior to treatment start date. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy at least six weeks ago) are exempt from pregnancy testing. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
  10. Male and female subjects of reproductive potential who agree to use both a highly effective method of birth control (e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy.

The following are UNACCEPTABLE forms of contraception for females of childbearing potential:

  • natural family planning (rhythm method)
  • breastfeeding
  • fertility awareness
  • withdrawal For subjects, these birth control requirements must be adhered to for 4 months after the last dose of umbralisib and 12 months after the last dose of ublituximab, whichever is later.

Regulatory Criteria

1. Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.

Exclusion Criteria:

Disease-Related

  1. Transformed lymphoma; if clinical evidence of transformed lymphoma is present, transformation should be ruled out by biopsy of the suspicious lymph node/lesion
  2. Prior treatment for follicular lymphoma or marginal zone lymphoma (Except: involved field or site radiation therapy is allowed)
  3. Medically apparent central nervous system lymphoma or leptomeningeal disease
  4. Tumor burden where administration of other FDA approved anti-CD20 antibodies like singleagent rituximab would be inappropriate.
  5. Patients in need of immediate cytoreduction with chemotherapy based regimen.

Concurrent Conditions

  1. Evidence of chronic active Hepatitis B (HBV, not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active Hepatitis C infection (HCV), active cytomegalovirus (CMV), or known history of HIV (or positive HIV test during screening). If HBc antibody is positive, the subject must be evaluated for the presence of HBV DNA by PCR. If HCV antibody is positive, the subject must be evaluated for the presence of HCV RNA by PCR. See Appendix: HEPATITIS B SEROLOGIC TEST RESULTS. If the subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence of CMV DNA by PCR. Subjects with positive HBc antibody and negative HBV DNA by PCR are eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are eligible (subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by PCR are eligible).
  2. Ongoing drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by stones, or cirrhosis of the liver
  3. Inflammatory bowel disease (such as Crohn's disease or ulcerative colitis)
  4. Irritable bowel syndrome with greater than 3 loose stools per day as a baseline
  5. Active autoimmune disease requiring ongoing immunosuppressive therapy including systemic corticosteroids (prednisone or equivalent ≤10 mg daily allowed as clinically warranted) within 12 months prior to enrollment. Patients are allowed to use topical or inhaled corticosteroids or levothyroxine for hypothyroidism or hypogylcemic agents for diabetes mellitis.

  6. Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:

    • Symptomatic, or history of documented congestive heart failure NYHA (New York Heart Association) functional classification III-IV [see Appendix: New York Heart Association Classifications]
    • Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, CHF, or myocardial infarction within 6 months of enrollment.
    • Concomitant use of medication known to cause QT prolongation or torsades de pointes should be used with caution and at investigator discretion.
    • Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting within 6 months of enrollment.
  7. Women who are pregnant or lactating

  8. History of other malignancies (including myelodysplastic syndromes) except:

    • malignancy treated with curative intent and with no known active disease present for >2 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
    • adequately treated non-melanoma skin cancer without evidence of disease
    • adequately treated carcinoma in situ without evidence of disease
    • localized prostate cancer and PSA <1.0 mg/dL on 2 consecutive measurements at least 3 months apart with the most recent one being within 4 weeks of study entry

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ublituximab Only
Treatment-Naive Stage II (non-contiguous), Stage III, Stage IV FL + MZL will receive Ublituximab 900mg IV weekly x 4 doses. End of treatment assessment 8 weeks post last dose of single agent ublituximab will be performed.
Drug: Ublituximab

Ublituximab will be administered as an intravenous infusion through a dedicated line. All infusions will be administered per institutional guidelines.

During ublituximab monotherapy (initial treatment), Cycle 1 Day 1 administration time frame: Over 4 hours. Cycle 1 days 8 and 15 will be over 3 hours, and Cycle 1 Day 22 will be over 90 minutes. During combination treatment with umbralisib, ublituximab will be administered over 90 minutes.
Experimental: Ublituximab first, then Ublituximab and Umbralisib
Patients who achieve less than a complete response will receive a combination of ublituximab AND umbralisib for a total of 12 cycles. (In the combination arm ublituximab will be administered on day 1,8 and 15 on cycle 1 and on day 1 on each cycle thereafter. Umbralisib will be administered at 800 mg daily for 12 cycles)
Drug: Ublituximab

Ublituximab will be administered as an intravenous infusion through a dedicated line. All infusions will be administered per institutional guidelines.

During ublituximab monotherapy (initial treatment), Cycle 1 Day 1 administration time frame: Over 4 hours. Cycle 1 days 8 and 15 will be over 3 hours, and Cycle 1 Day 22 will be over 90 minutes. During combination treatment with umbralisib, ublituximab will be administered over 90 minutes.

Drug: Umbralisib
Umbralisib will be administered orally once daily within 30 minutes of starting a meal.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Complete Response Rate (CR) at 8 Weeks Post Single Agent Induction
Time Frame: 8 weeks post induction

Number of subjects that reached a complete response at the end of single agent induction as defined by a Lugano score of 3 or less on arm MONO - Monotherapy: Ublituximab.

Complete response assessed via PET CT scan utilizing the Lugano-Deauville Criteria where none of the lymphoma lesions had FDG ( FluoroDeoxyglucose) avidity greater than the liver uptake.

Patients who did not reach complete response at this point were then bridged to arm COMBO - Combotherapy: Ublituximab + Umbralisib.
8 weeks post induction
Number of Participants With Complete Response Rate (CR) at up to 12 Months Post MONO - Monotherapy: Ublituximab or Combotherapy: Ublituximab + Umbralisib.
Time Frame: up to 12 months post induction

Number of subjects that reached a complete response at up to 12 months post induction as defined by a Lugano score of 3 or less on arms MONO - Monotherapy: Ublituximab.OR Combotherapy: Ublituximab + Umbralisib.

Complete response assessed via PET CT scan utilizing the Lugano-Deauville Criteria where none of the lymphoma lesions had FDG ( FluoroDeoxyglucose) avidity greater than the liver uptake.
up to 12 months post induction

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rates (ORR) for Number of Participants
Time Frame: up to 12 months post induction

Overall Response Rate for number of subjects as defined by a Lugano score of 3 or less on arms MONO - Monotherapy: Ublituximab.OR Combotherapy: Ublituximab + Umbralisib.

Overall response rate assessed via PET CT utilizing Lugano deauvile criteria where lymphoma lesions had responded and would include complete response, partial response (> 50% improvement) and stable disease (less than 50 % response)
up to 12 months post induction

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Colorado, Denver

Investigators

  • Principal Investigator: Manali Kamdar, MD, University of Colorado, Denver

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 23, 2020

Primary Completion (Actual)

July 14, 2022

Study Completion (Actual)

July 14, 2022

Study Registration Dates

First Submitted

August 7, 2020

First Submitted That Met QC Criteria

August 10, 2020

First Posted (Actual)

August 11, 2020

Study Record Updates

Last Update Posted (Actual)

March 21, 2024

Last Update Submitted That Met QC Criteria

March 19, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 18-2128.cc
  • NCI-2021-00405 (Other Identifier: CTRP)
  • U2-NTG-009 (Other Identifier: TG Therapeutics Inc.)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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