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Indolent Non-Hodgkin's LymphomaPhase 2PrE0401NCT01889797

Phase II Randomized Trial Comparing GA101 and Rituximab in Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma

A Phase 2 study testing Arm A: Rituximab and Arm B: GA101 in people with Indolent Non-Hodgkin's Lymphoma, run by PrECOG, LLC. at 28 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

Patients with previously untreated low tumor burden indolent Non-Hodgkin's Lymphoma (NHL) will receive either rituximab or GA101 weekly for 4 weeks followed by re-staging to determine response. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Indolent Non-Hodgkin's Lymphoma
What is being tested?
Arm A: Rituximab and Arm B: GA101
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
28 sitesUnited States
Study dates
Dec 2013to Aug 2016
Phase
Phase 2
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

  • Registration: Patients having both diffuse and follicular architectural elements will be considered eligible if the histology is predominantly follicular (≥ 50% of the cross-sectional area), and there is no evidence of transformation to a large cell histology.
  • Biopsy-proven diagnosis of Grade 1 or 2 follicular non-Hodgkin's lymphoma with no evidence of transformation to large cell histology.
  • Meet criteria for Low Tumor Burden:
  • No nodal or extra nodal mass ≥ 7 centimeter (cm)
  • <3 nodal masses >3 cm in diameter
  • No systemic symptoms or B symptoms
Show all 43Show fewer
  • No splenomegaly >16 cm by CT scan
  • No risk of compression of a vital organ.
  • No leukemic phase with >5000/mm³ circulating lymphocytes.
  • No cytopenias defined as:
  • Platelets <100,000/mm³
  • Hemoglobin (Hgb) <10 g/dL
  • Absolute Neutrophil Count (ANC) <1500/mm³
  • Must have Stage III or Stage IV disease.
  • Baseline measurements/evaluations obtained within 6 weeks of registration. Patient must have at least one objective measurable disease parameter.
  • Age ≥ 18 years.
  • Eastern Oncology Cooperative Group Performance Status 0-1.
  • Must not have received investigational agents within 30 days of registration.
  • Signed Institutional Review Board (IRB)-approved informed consent.
  • Willing to provide blood samples for research purposes.
  • Women must not be pregnant or breastfeeding.
  • Women of childbearing potential and sexually active males must use an accepted and effective method of contraception.
  • No prior chemotherapy, radiotherapy or immunotherapy for lymphoma.
  • No prior treatment with cytotoxic drugs or rituximab for a previous cancer or another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody.
  • No prior use of any monoclonal antibody within 3 months of randomization.
  • No history of severe allergic/anaphylactic reactions to humanized/murine monoclonal antibodies or known sensitivity/allergy to murine products.
  • No history of prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least 2 years and did not require treatment with cytotoxic drugs or rituximab.
  • No major surgery within 4 weeks prior to randomization, other than for diagnosis.
  • Must be Human Immunodeficiency Virus (HIV) negative.
  • Have adequate organ function without growth factor and/or transfusion support within ≤ 2 weeks prior to registration:
  • ANC ≥ 1500/mm³
  • Hgb ≥ 10 g/dL
  • Platelets ≥ 100,000/mm³
  • Serum Creatinine ≤ 2x Upper Limit Normal (ULN)
  • Total Bilirubin ≤ 2x ULN
  • AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ≤ 5x ULN
  • PTT (Partial Thromboplastin Time) or aPTT (activated Partial Thromboplastin Time) >1.5x the ULN in the absence of a lupus anticoagulant
  • INR (International Normalized Ratio) >1.5x the ULN in the absence of therapeutic anticoagulation
  • No active, uncontrolled infections (afebrile for ≥ 48 hours off antibiotics).
  • Must not receive immunization with attenuated live vaccines within 28 days prior to registration or during the study period.
  • Must be tested for hepatitis B surface antigen (HBsAg) and total hepatitis B core antibody (anti-HBc) within 2 weeks of registration. Patients who are chronic carriers of HBsAg and anti-HBc are excluded.
  • Must be tested for hepatitis C antibody within 2 week of registration. If this test is positive, patients are excluded unless a hepatitis C virus ribonucleic acid (HCV RNA) is negative.
  • No evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (i.e., severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease.

Who cannot join

None listed.

Trial locations and contacts

28 sites in 1 country.

28 sites in 1 country

United States28 sites

  • St. Joseph Mercy Health System

    Ann Arbor, Michigan, 48106

  • Greater Baltimore Medical Center

    Baltimore, Maryland, 21204

  • Tufts Medical Center

    Boston, Massachusetts, 02111

  • Aultman Hospital

    Canton, Ohio, 44710

  • Charleston Area Medical Center (CAMC)

    Charleston, West Virginia, 25304

  • University of Virginia

    Charlottesburg, Virginia, 22908

  • University Hospitals Case Medical Center

    Cleveland, Ohio, 44106

  • Geisinger Medical Center

    Danville, Pennsylvania, 17822

  • Decatur Memorial Hospital

    Decatur, Illinois, 62526

  • Marin Cancer Care

    Greenbrae, California, 94904

  • Indiana University

    Indianapolis, Indiana, 46202

  • Gundersen Health System

    La Crosse, Wisconsin, 54601

  • Dean Clinic

    Madison, Wisconsin, 53717

  • University of South Alabama

    Mobile, Alabama, 36604

  • Ochsner Cancer Institute

    New Orleans, Louisiana, 70121

  • Missouri Valley Cancer Consortium

    Omaha, Nebraska, 68106

  • Fox Chase Cancer Center

    Philadelphia, Pennsylvania, 19111

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Metro MN CCOP

    Saint Louis Park, Minnesota, 55416

  • St. Joseph's/Candler Health System

    Savannah, Georgia, 31405

  • Siouxland Hematology Oncology Associates

    Sioux City, Iowa, 51101

  • Montefiore Medical Center

    The Bronx, New York, 10467

  • Toledo Community Oncology Program

    Toledo, Ohio, 43617

  • Carle Cancer Center

    Urbana, Illinois, 61801

  • ProHealth Care, Inc.

    Waukesha, Wisconsin, 53188

  • Aurora Health Care

    Wauwatosa, Wisconsin, 53266

  • Reading Hospital

    West Reading, Pennsylvania, 19611

  • Susquehanna Health Cancer Center

    Williamsport, Pennsylvania, 17701

Other trials in United States

About this study

Official title: Phase II Randomized Trial Comparing GA101 (Obinutuzumab) and Rituximab in Patients With Previously Untreated Low Tumor Burden Indolent Non-Hodgkin's Lymphoma

Patients with previously untreated low tumor burden indolent Non-Hodgkin's Lymphoma (NHL) will receive either rituximab or GA101 weekly for 4 weeks followed by re-staging to determine response.

Rituximab, an anti-CD20 chimeric antibody, was approved by the United States Food and Drug Administration in 1998 for the treatment of patients with relapsed low-grade B-cell lymphomas. Clinically, four weekly doses of rituximab have proven to be well tolerated and effective in previously untreated as well as relapsed patients with low-grade lymphoma.

Read more

GA101 is an anti-CD20 humanized and glyco-engineered monoclonal antibody. GA101 has been shown to have increased antibody-dependent cellular cytotoxicity (ADCC) and direct cell-death induction compared to Rituximab. It is possible that GA101 may have greater efficacy than rituximab.

PrE0401 Sub-Study Evaluation of Corrected QT (QTc) Interval and Pharmacokinetic Parameters in Patients Participating in GA101 (Obinutuzumab)

Approximately twenty-five patients randomized to GA101 may participate in the sub-study. Electrocardiograms and blood samples will be obtained.

Read the detailed description

According to the American Cancer Society, it is estimated that approximately 70,800 individuals will be diagnosed with non-Hodgkin's lymphoma (NHL) and over 18,990 men and women will die of the disease in 2014. The survival rates for patients with indolent NHL remained unchanged from the 1950s through the early 1990s, but recent evidence suggests that outcomes are improving. Indolent NHL is a particular challenge because it is an incurable disease requiring multiple treatments; yet relatively long survivals elevate the importance of quality of life associated with treatment.

Agents such as rituximab are active in patients with a low burden of disease and result in high response rates and durable remissions for most patients. However, the optimal therapeutic approach to patients with low-grade lymphoma with a low disease burden is controversial as conventional chemotherapy also results in high rates of response. Regardless of whether patients receive immunotherapy, chemotherapy, or a combination thereof, they unfortunately exhibit a continuing pattern of disease relapse and the median survival for newly diagnosed patients is between 7-10 years.

Rituximab and GA101 both target the CD20 antigen. The CD20 antigen is located on the surface of normal and malignant B-cell lymphocytes. An attractive feature of this target is that CD20 is not on hematopoietic stem cells, nor is it expressed in any great extent on other normal body tissues.

Studies in vitro have shown that rituximab predominantly induces antibody dependent cellular cytotoxicity (ADCC), but also binds complement and directly induces apoptosis in lymphoma cells.

GA101 shows increased ADCC related to an improved binding of the GA101 to the different allotypes expressed by natural killer cells and monocytes. It also has increased direct cell-death related to an elbow hinge amino acid exchange and Type II binding of the CD20 epitope. The safety of GA101 in NHL so far appears to be similar to that observed with rituximab in patients with NHL, except for a higher incidence of infusion-related reactions.

Depletion of malignant B-cells using anti-CD20 monoclonal antibodies has an acceptable safety profile, particularly in patients with low-grade B-cell lymphomas with a low disease burden. To determine whether treatment with GA101 results in better outcomes than that seen with rituximab and to determine which anti-CD20 antibody to utilize in future studies, we will conduct a randomized Phase II trial of rituximab and GA101 in patients with previously untreated low-grade lymphoma. Patients will receive either rituximab or GA101 weekly for 4 weeks followed by re-staging. The endpoints of the study will be the Complete Response (CR), Overall Response Rate (ORR), time to next treatment, progression free survival (PFS), and safety of each treatment arm.

PrE0401 Sub-Study Evaluation of Corrected QT (QTc) Interval and Pharmacokinetic Parameters in Patients Participating in GA101 (Obinutuzumab)

Patients randomized to GA101 and who consent to the sub-study will have electrocardiograms obtained pre and post Week 1 and Week 4 to investigate the effect of GA101 on QTc interval. Pharmacokinetic blood samples will also be done to evaluate serum concentrations of GA101 at the same time-points.

Being tested
Arm A: Rituximab, Arm B: GA101
Keywords
Untreated Non-Hodgkin's Lymphoma, Low Tumor Burden Non-Hodgkin's Lymphoma, NHL, Indolent, Rituximab, Rituxan, GA101, Obinutuzumab

What participants receive

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

  • Arm A: RituximabBiological

    Also called IDEC-C2B8, Chimeric anti-CD20 monoclonal antibody, Rituxan, NSC# 687451

    Rituximab 375 mg/m² IV x 4 weekly doses.

  • Arm B: GA101Biological

    Also called Obinutuzumab, RO5072759, huMAB<CD20>

    GA101 1,000 mg (flat dose) IV x 4 weekly doses.

Study groups in NCT01889797
Study groupRoleWhat they receive
Arm A: RituximabActive comparatorRituximab 375 mg/m² IV weekly for 4 weeks.
Receives: Biological: Arm A: Rituximab
Arm B: GA101ExperimentalGA101 1,000 mg IV weekly for 4 weeks.
Receives: Biological: Arm B: GA101

What is being measured

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

  1. Complete Response (CR) Rate

    Positron Emission Tomography (PET)-documented CR rates after induction therapy (weekly treatment x 4 weeks with GA101 or rituximab)

    Definitions for clinical response are modified from the Revised Response Criteria for Malignant Lymphoma (Cheson BD, et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol 2007; 25(5): 579-86). Lymph node measurements were taken from CT, CT portion of the PET/CT, or MRI scans where applicable. CR is defined as complete disappearance of all evidence of disease; PR as a >50% decrease in the sum of the products of the maximal perpendicular diameters of measured lesions (SPD) and no new sites; SD as failure to attain CR/PR or PD; and PD as any new lesion >1.5cm in any axis or ≥50% increase in previously involved sites.

    Measured: Re-staging (week 12, 13 or 14) and during follow-up if physician feels patient is subsequently in CR for up to 4 years

Secondary outcomes (3)

  1. PET Response Rate

    PET response rate [PET-documented CR + Partial Response (PR)] based on PET scan results. Patients with unevaluable disease were included in the denominator.

    Measured: Re-staging (week 12, 13 or 14)

  2. Overall Response Rate

    Overall response rate (CR + PR by Cheson criteria) at re-staging (including bone marrow biopsy if CR suspected) by PET and Neck, Chest, Abdomen and Pelvic Computed Tomography (CT) scan. Patients with unevaluable disease were included in the denominator.

    Measured: Baseline and Re-staging (week 12, 13 or 14)

  3. Progression Free Survival (PFS)

    CT scan every 3 months for 2 years, then every 6 months until progression. Compare PFS in each treatment arm.

    Progressive disease (PD) was defined using Cheson criteria as described in the Primary Outcome section above. Progression-free survival (PFS) was defined as the time from start of treatment to the documentation of PD or death, whichever occurs first. Patients alive and without PD were censored at the date of last disease assessment.

    Measured: Percent of participants alive and progression-free at 1 year

Timeline

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

  1. First posted28 Jun 2013 (estimated)
  2. Study startDec 2013
  3. Primary completionApr 2016
  4. Study completionAug 2016

Why it stopped: Closed due prolonged enrollment timelines

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
32 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01889797
Sponsor's protocol ID
PrE0401
Other IDs
BO25454
Acronym
PrE0401
Status last verified
Mar 2017
First submitted
26 Jun 2013
Last updated
5 May 2017
Data monitoring committee
Yes
Individual data sharing
No: Data is proprietary.

Publications

  • Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. doi: 10.1200/JCO.2002.08.674.

    PubMed 12377971

  • Beers SA, Chan CH, French RR, Cragg MS, Glennie MJ. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol. 2010 Apr;47(2):107-14. doi: 10.1053/j.seminhematol.2010.01.001.

    PubMed 20350657

  • Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S, Grau R, Gerdes C, Nopora A, van Puijenbroek E, Ferrara C, Sondermann P, Jager C, Strein P, Fertig G, Friess T, Schull C, Bauer S, Dal Porto J, Del Nagro C, Dabbagh K, Dyer MJ, Poppema S, Klein C, Umana P. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood. 2010 Jun 3;115(22):4393-402. doi: 10.1182/blood-2009-06-225979. Epub 2010 Mar 1.

    PubMed 20194898

  • Salles GA, et al. Efficacy and Safety of Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Indolent Non-Hodgkin's Lymphoma: Results from a Phase I/II Study (BO20999) American Society of Hematology Annual meeting 2011 Abstract 268.

  • Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized Phase II Trial Comparing Obinutuzumab (GA101) With Rituximab in Patients With Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Final Analysis of the GAUSS Study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. doi: 10.1200/JCO.2014.59.2139. Epub 2015 Aug 17.

    PubMed 26282650

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Arm A: Rituximab and Arm B: GA101 in people with Indolent Non-Hodgkin's Lymphoma, run by PrECOG, LLC. at 28 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 43 inclusion and 0 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 5 May 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 28 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 5 May 2017). 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?

Complete Response (CR) Rate (time frame: Re-staging (week 12, 13 or 14) and during follow-up if physician feels patient is subsequently in CR for up to 4 years). 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 NCT01889797, which also lists 5 linked publications.

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 5 May 2017.

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