Ofatumumab vs. Rituximab Salvage Chemoimmunotherapy followed by ASCT in Relapsed or Refractory DLBCL (ORCHARDD Trial/ Phase III)

Trial Purpose and Description

Trial Purpose

As rituximab-based regimens have become standard first-line treatment in CD20 positive DLBCL, the efficacy of rituximab combined with salvage chemotherapy in the secondline setting has decreased and there is a need for new therapies in patients progressing or relapsing after first-line rituximab-based therapy. Replacement of rituximab with ofatumumab in the second-line setting, following progression/relapse after first-line rituximab-containing regimens, offers the potential to overcome relative or complete rituximab resistance and thus improve response rates, the ability to proceed to consolidative HDT/ASCT, and overall survival.

This study is being conducted to compare the efficacy and safety of ofatumumab in addition to salvage chemotherapy versus rituximab in addition to salvage chemotherapy in CD20 positive DLBCL or grade 3b FL subjects progressing, relapsing or with persistent lymphoma after first-line treatment with rituximab combined with an anthracycline- or anthracenedione-based chemotherapy regimen.

Primary objective:

• To evaluate the progression-free survival (PFS) in subjects receiving ofatumumab in addition to salvage chemotherapy (O-chemo) compared to subjects receiving rituximab in addition to salvage chemotherapy (R-chemo).

Secondary objectives. To evaluate the following in subjects receiving O-chemo compared to subjects receiving R-chemo:

• Overall and complete response rate after salvage chemoimmunotherapy.

• Overall and complete response rate three months after ASCT.

• Event-free survival.

• Overall survival.

• Number of subjects with inadequate mobilisation of autologous stem cells (<2.0 million CD34+ cells/kg) prior to administration of high dose therapy (HDT).

• Number of subjects completing ASCT.

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Participation Guidelines

Eligibility Criteria

INCLUSION CRITERIA

1. CD20 positive DLBCL or grade 3b follicular lymphoma (FL) at original diagnosis. If an evaluable biopsy or fine needle aspiration (FNA) is performed prior to enrolment to the study it must confirm CD20 positive DLBCL or grade 3b FL. Note: If evidence emerges that the binding of the immunohistochemical antibody to CD20 can be blocked by rituximab, demonstration of CD20 positivity in the repeat biopsy/FNA will not be required.

2. Refractory to, or relapsed following, first-line treatment with rituximab concurrently with anthracycline- or anthracenedione-based chemotherapy.

Relapse is defined as:

• Biopsy (preferred) or FNA confirmed DLBCL or grade 3b FL after a complete response (CR) or unconfirmed complete response (CRu). However, for subjects relapsing during first-line treatment, biopsy/FNA reconfirmation of the lymphoma is recommended but not mandatory.

Subjects must have received rituximab concurrently with at least 6 cycles of chemotherapy. However, subjects with stage I/II disease will be eligible if they have received rituximab concurrently with at least 3 cycles of chemotherapy and definitive involved-field radiation therapy#.

Refractory disease must fulfill one of the following:

• continuing partial response (PR) from termination of first-line treatment. It is strongly recommended the lymphoma be reconfirmed by biopsy (preferred) or FNA, however, if these procedures are deemed to be inappropriate, then HOVON may determine eligibility following review of the imaging results and disease history.

Subjects must have received rituximab concurrently with at least 6 cycles of chemotherapy. However, subjects with stage I/II disease will be eligible if they have received rituximab concurrently with at least 3 cycles of

chemotherapy and definitive involved-field radiation therapy#.

• continuing stable disease (SD) from termination of first-line treatment. Reconfirmation of the lymphoma by biopsy (preferred) or FNA is recommended but not mandatory.

Subjects must have received rituximab concurrently with at least 3 cycles of chemotherapy#.

• progressive disease (PD). Biopsy or FNA reconfirmation of the lymphoma is recommended but not mandatory.

Note: Disease response to first-line treatment is recommended to be determined according to Revised Response Criteria for Malignant Lymphoma [Cheson, 2007] or International Workshop Response criteria for NHL [Cheson, 1999]. For guidance on the adequacy of dosing of rituximab during first-line therapy refer to the SPM.

3. Baseline FDG-PET scans must demonstrate positive lesions compatible with CT defined anatomical tumor sites.

4. CT scan showing at least:

• 2 or more clearly demarcated lesions/nodes with a long axis >1.5cm and short axis ≥1.0cm

5. Age ≥18

6. ECOG performance status 0, 1, or 2.

7. Eligible for high dose chemotherapy and ASCT.

8. Resolution of toxicities from first-line therapy to a grade that in the opinion of the investigator does not contraindicate study participation.*

9. Signed written informed consent.

EXCLUSION CRITERIA

1. Any previous cancer therapy for the lymphoma, with the exception of:

• First-line treatment with rituximab and an anthracycline- or anthracenedionebased chemotherapy.

• Monotherapy rituximab, dosed prior to first-line rituximab combined with chemotherapy, or as maintenance therapy.

• Radiotherapy as part of the first-line treatment plan.

• Radiotherapy to a limited field at a maximum dose of ≤10Gy to control lifethreatening symptoms.

• Prophylactic testicular radiotherapy for testicular lymphoma.

• Intrathecal chemotherapy for the prophylaxis of CNS disease.

2. Received any of the following treatments within two weeks prior to start of study therapy (unless otherwise stated):

• Anti-cancer cytotoxics (e.g. alkylating agents, anti-metabolites, purine analogues)

• Radiotherapy unless it is to a limited field at a maximum dose of ≤10Gy to control life-threatening symptoms.

3. 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 unless in the opinion of the investigator it does not contraindicate participation in this study.*

4. Planned post-randomisation glucocorticoid therapy, unless

• specified by the protocol

• administered in doses ≤1mg/kg/day prednisolone (or equivalent dose of other glucocorticoid-refer to the SPM for glucocorticoid equivalent doses)

• administered as inhalation therapy for mild COPD or asthma.

5. History of significant cerebrovascular disease or event with significant symptoms or sequelae, unless in the opinion of the investigator it does not contraindicate participation in the study.*

6. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomisation, congestive heart failure (NYHA III-IV), a current LVEF of <40%, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities, unless in the opinion of the investigator it does not contraindicate participation in the study.*

7. Significant concurrent, uncontrolled medical condition that in the opinion of the investigator contraindicates participation in this study.*

8. Known lymphoma involvement of the CNS.

9. Known or suspected hypersensitivity to study treatments that in the opinion of the investigator contraindicates their participation.*

10. Known HIV positivity.

11. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive the subject will be excluded.

12. Active hepatitis C infection.

13. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis and tuberculosis.

14. Other past or current malignancy within 2 years prior to randomization unless in the opinion of the investigator it does not contraindicate participation in the study. Subjects who have been free of malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma, are eligible.*

15. Prior treatment with anti-CD20 monoclonal antibodies with the exception of rituximab.

16. Screening laboratory values:

• platelets <100x109/L (unless due to lymphoma involvement of the bone marrow)

• neutrophils <1.5x109/L (unless due to lymphoma involvement of the bone marrow)

• creatinine >2.0 times upper normal limit (unless due to lymphoma or unless creatinine clearance >60mL/min)

• total bilirubin >1.5 times upper normal limit (unless due to lymphoma or a known history of Gilbert’s disease)

• ALT >2.5 times upper normal limit (unless due to lymphoma)

• alkaline phosphatase >2.5 times upper normal limit (unless due to lymphoma )

17. Subjects known or suspected of being unable to comply with the study protocol.

18. Pregnant or lactating women. Women of childbearing potential must have a negative pregnancy test at screening.

19. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence.

20. Male subjects unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Sponsor:

GlaxoSmithKline

Dates:

September 2012

Last Updated:

Study HIC#:

1202009794

Clinicaltrials.gov ID: Yale8885570