Clinical trial NCT01626352: Study of Bendamustine and Ofatumumab in Elderly Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy
Official title: Phase II Study of Bendamustine and Ofatumumab in Elderly Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diffuse Large B-Cell Lymphoma
Keywords: Diffuse Large B-Cell Lymphoma
Ofatumumab
Bendamustine
Lead sponsor: SCRI Development Innovations, LLC
Sponsor class: OTHER
Collaborators: name: Novartis
name: GlaxoSmithKline
name: Cephalon
First posted: 2012-06-22
Enrollment: 22
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-arm, Phase II study designed to enroll and treat up to 64 patients. All patients in this study will receive ofatumumab and bendamustine as an IV infusion for 6 cycles (a cycle is defined as 21 days in length). Patients will receive as an IV infusion bendamustine Days 1 and 2 of Cycles 1 through 6 and ofatumumab Days 1 and 8 during Cycle 1 only and on Day 1 of Cycles 2 through 6.

Detailed description: While R-CHOP has improved survival and is considered standard of care for patients with DLBCL, the toxicities associated with R-CHOP are substantial in the elderly population. This is one of several reasons the outcome of older patients is worse than the corresponding younger patients. Bendamustine is an alkylating agent which causes intra- and inter-strand cross-links between DNA bases. Ofatumumab is a fully human anti-CD 20 antibody well tolerated by elderly patients. Ofatumumab targets a novel epitope of the CD20 molecule on B cells and remains on the cell surface twice as long as rituximab. The combination of both agents allows for a potentially efficacious, less toxic regimen.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed CD20-positive DLBCL.
2. Newly diagnosed, stage III-IV DLBCL considered poor candidates for R-CHOP.
3. Age \>=70 years
4. At least one of the following criteria:

   * ECOG PS 2
   * Cardiac compromise precluding anthracycline therapy
   * Previous anthracycline therapy for other malignancy precluding further anthracycline therapy.
   * Severe coexisting medical problems
   * General frailty
5. ECOG 0-2
6. Measurable disease with at least one bidimensional lymph node or tumor mass \>1.5 cm in the longest diameter that can be followed for response as a target lesion as measured by CT
7. Patients must be HBV sAg and HBV cAb negative within 6 weeks of screening.
8. Patient must understand and voluntarily sign the IRB-approved informed consent.
9. Life expectancy \>= 3 months
10. Laboratory parameters:

    * Absolute neutrophil count \>=1,000 cells/mm3
    * Platelet count \>=75,000 cells/mm3
    * Hemoglobin \>=8 g/dL
    * Creatinine \<=2.0 mg/dL or Creatinine Clearance \>= 40 mL/min (calculated or 24 hour urine sample)
    * AST/SGOT \<=2.0 x ULN (\<=5.0 x ULN if secondary to lymphoma)
    * ALT/SGPT \<=2.0 x ULN (\<=5.0 x ULN if secondary to lymphoma)
    * Bilirubin level of \<2.0 mg/dL unless secondary to Gilbert's disease (or pattern consistent with Gilbert's)

Exclusion Criteria:

1. Patients with active/symptomatic central nervous system (CNS) involvement based on clinical evaluation by lumbar puncture, PET, CT or MRI.
2. Known sensitivity to bendamustine or any component of bendamustine.
3. Known anaphylaxis or sensitivity to ofatumumab.
4. Major surgery within 28 days of Cycle 1, Day 1. Patients undergoing minor surgery within 7 days of Cycle 1, Day 1. (no wait needed for port placement)
5. Prior chemotherapy, immunotherapy, or irradiation for lymphoma.
6. Prior use of investigational anti-cancer agents for lymphoma.
7. HIV-related lymphoma.
8. Known active HIV or HCV infection, or known seropositivity for HIV, or current or chronic HBV or HCV infection. HBV test required at screening or a negative result within 6 weeks of screening.
9. Concurrent active or history of other malignancies, except non-melanoma skin cancer or carcinoma in situ of cervix or breast. Patients with previous malignancies are eligible provided they have been treated with curative intent and disease free for \>= 1 year.
10. Serious (grade 3-4), active, intercurrent infection requiring therapy, or deep seated or systemic mycotic infections.
11. Myocardial infarction within 6 months prior to registration or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities, in the judgment of the Investigator.
12. Concurrent uncontrolled serious medical or psychiatric conditions likely to interfere with participation in this clinical study, in the judgment of the Investigator
13. Patients who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
14. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study.
15. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
16. Male patients unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Primary outcomes:
measure: Number of Patients With a Complete Response
timeFrame: 18 months
Secondary outcomes:
measure: Duration of Response
timeFrame: After cycles 3 and 6 of each 21-day cycle and every 3 months thereafter until disease progression or relapse from complete response for up to 38 months
measure: Time to Progression (TTP)
timeFrame: After cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter until progression or relapse from complete response for up to 40 months
measure: Overall Survival (OS)
timeFrame: every 3 cycles during treatment and every 3 months thereafter until progression or death from any cause, projected 18 months
measure: Overall Response (OR)
timeFrame: after cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter, projected 18 months
measure: Number of Patients With Treatment-Related Adverse Events (AEs) as a Measure of Safety
timeFrame: after cycles 3 and 6 of each 21-day cycle, and up to 30 days after last dose, projected 24 weeks
measure: Progression-free Survival
timeFrame: After cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter until progression or relapse from complete response for up to 40 months
Other outcomes:
Locations:
city: Fort Myers
country: United States
facility: Florida Cancer Specialists-South
state: Florida
city: Pensacola
country: United States
facility: Woodlands Medical Specialists
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists North
state: Florida
city: Titusville
country: United States
facility: Space Coast Cancer Center
state: Florida
city: Terre Haute
country: United States
facility: Providence Medical Group
state: Indiana
city: Terre Haute
country: United States
facility: RHHP/Hope Cancer Center
state: Indiana
city: Grand Rapids
country: United States
facility: Grand Rapids Oncology Program
state: Michigan
city: Lawton
country: United States
facility: Cancer Centers of Southwest Oklahoma
state: Oklahoma
city: Oklahoma City
country: United States
facility: Oklahoma University
state: Oklahoma
city: Chattanooga
country: United States
facility: Tennessee Oncology-Chattanooga
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
Study officials:
affiliation: SCRI Development Innovations, LLC
name: Ian Flinn, MD, PhD
role: STUDY_CHAIR
References:
citation: Aapro MS, Cameron DA, Pettengell R, Bohlius J, Crawford J, Ellis M, Kearney N, Lyman GH, Tjan-Heijnen VC, Walewski J, Weber DC, Zielinski C; European Organisation for Research and Treatment of Cancer (EORTC) Granulocyte Colony-Stimulating Factor (G-CSF) Guidelines Working Party. EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphomas and solid tumours. Eur J Cancer. 2006 Oct;42(15):2433-53. doi: 10.1016/j.ejca.2006.05.002. Epub 2006 Jun 5.
citation: Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
citation: Ansell SM, Falkson G, van der Merwe R, Uys A. Chronological age is a multifactorial prognostic variable in patients with non-Hodgkin's lymphoma. Ann Oncol. 1992 Jan;3(1):45-50. doi: 10.1093/oxfordjournals.annonc.a058068.
citation: Armitage JO, Potter JF. Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: increased complications with advancing age. J Am Geriatr Soc. 1984 Apr;32(4):269-73. doi: 10.1111/j.1532-5415.1984.tb02020.x.
citation: Balducci L, Repetto L. Increased risk of myelotoxicity in elderly patients with non-Hodgkin lymphoma. Cancer. 2004 Jan 1;100(1):6-11. doi: 10.1002/cncr.11861. No abstract available.
citation: Chang JE, Seo S, Kim KM, Werndli JE, Bottner WA, Rodrigues GA, Sanchez FA, Saphner TJ, Longo WL, Kahl BS. Rituximab and CHOP chemotherapy plus GM-CSF for previously untreated diffuse large B-cell lymphoma in the elderly: a Wisconsin oncology network study. Clin Lymphoma Myeloma Leuk. 2010 Oct;10(5):379-84. doi: 10.3816/CLML.2010.n.071.
citation: Chow KU, Sommerlad WD, Boehrer S, Schneider B, Seipelt G, Rummel MJ, Hoelzer D, Mitrou PS, Weidmann E. Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases. Haematologica. 2002 Jan;87(1):33-43.
citation: Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. doi: 10.1056/NEJMoa011795.
citation: Coiffier B, Radford J, Bosly A, Martinelli G, Verhoef G, Barca G, Davies A, Decaudin D, Gallop-Evans E, Padmanabhan-Iyer S, Van Eygen K, Wu KL, Gupta IV, Lin TS, Goldstein N, Jewell RC, Winter P, Lisby S; 415 study investigators. A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma. Br J Haematol. 2013 Nov;163(3):334-42. doi: 10.1111/bjh.12537. Epub 2013 Aug 23.
citation: Dixon DO, Neilan B, Jones SE, Lipschitz DA, Miller TP, Grozea PN, Wilson HE. Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience. J Clin Oncol. 1986 Mar;4(3):295-305. doi: 10.1200/JCO.1986.4.3.295.
citation: Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. doi: 10.1200/JCO.2005.09.131. Epub 2005 May 2.
citation: Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006 Jul 1;24(19):3121-7. doi: 10.1200/JCO.2005.05.1003. Epub 2006 Jun 5.
citation: Hainsworth JD, Flinn IW, Spigel DR, Clark BL, Griner PL, Vazquez ER, Doss HH, Shipley D, Franco LA, Burris HA 3rd, Greco FA; Sarah Cannon Oncology Research Consortium. Brief-duration rituximab/chemotherapy followed by maintenance rituximab in patients with diffuse large B-cell lymphoma who are poor candidates for R-CHOP chemotherapy: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma Leuk. 2010 Feb;10(1):44-50. doi: 10.3816/CLML.2010.n.004.
citation: Leoni LM, Bailey B, Reifert J, Bendall HH, Zeller RW, Corbeil J, Elliott G, Niemeyer CC. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008 Jan 1;14(1):309-17. doi: 10.1158/1078-0432.CCR-07-1061.
citation: International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993 Sep 30;329(14):987-94. doi: 10.1056/NEJM199309303291402.
citation: Lipschitz DA. Age-related declines in hematopoietic reserve capacity. Semin Oncol. 1995 Feb;22(1 Suppl 1):3-5. No abstract available.
citation: Ozer H, Armitage JO, Bennett CL, Crawford J, Demetri GD, Pizzo PA, Schiffer CA, Smith TJ, Somlo G, Wade JC, Wade JL 3rd, Winn RJ, Wozniak AJ, Somerfield MR; American Society of Clinical Oncology. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol. 2000 Oct 15;18(20):3558-85. doi: 10.1200/JCO.2000.18.20.3558. No abstract available.
citation: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. doi: 10.1016/S1470-2045(08)70002-0. Epub 2008 Jan 15.
citation: Strumberg D, Harstrick A, Doll K, Hoffmann B, Seeber S. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs. 1996 Jun;7(4):415-21. doi: 10.1097/00001813-199606000-00007.
citation: van Spronsen DJ, Janssen-Heijnen ML, Breed WP, Coebergh JW. Prevalence of co-morbidity and its relationship to treatment among unselected patients with Hodgkin's disease and non-Hodgkin's lymphoma, 1993-1996. Ann Hematol. 1999 Jul;78(7):315-9. doi: 10.1007/s002770050521.
citation: Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, Mitrou PS. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002 Aug;13(8):1285-9. doi: 10.1093/annonc/mdf189.
citation: Weidmann E, Neumann A, Fauth F, Atmaca A, Al-Batran SE, Pauligk C, Jager E. Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. Ann Oncol. 2011 Aug;22(8):1839-44. doi: 10.1093/annonc/mdq671. Epub 2011 Jan 21.
citation: Flinn IW, Erter J, Daniel DB, Mace JR, Berdeja JG. Phase II Study of Bendamustine and Ofatumumab in Elderly Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma Who Are Poor Candidates for R-CHOP Chemotherapy. Oncologist. 2019 Aug;24(8):1035-e623. doi: 10.1634/theoncologist.2019-0286. Epub 2019 May 9.