| CTRI Number |
CTRI/2012/06/002749 [Registered on: 27/06/2012] Trial Registered Prospectively |
| Last Modified On: |
16/07/2013 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug
Biological |
| Study Design |
Randomized, Parallel Group, Active Controlled Trial |
|
Public Title of Study
|
To compare the safety and efficacy of the relapsed diffuse large B cell lymphoma or grade 3b follicular lymphoma subject treated with Ofatumumab versus the same subject set treated with Rituximab |
|
Scientific Title of Study
|
Ofatumumab versus Rituximab Salvage Chemoimmunotherapy
followed by ASCT in Relapsed or Refractory DLBCL |
| Trial Acronym |
ORCHARRD: Ofatumumab versus Rituximab Salvage Chemoimmunotherapy
followed by ASCT in Relapsed or Refractory DLBCL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| OMB110928 amendment no.03 dated 16 Sep 2010 |
Protocol Number |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
|
| Designation |
|
| Affiliation |
|
| Address |
|
| Phone |
|
| Fax |
|
| Email |
|
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Jeroze Dalal |
| Designation |
General Manager |
| Affiliation |
GlaxoSmithKline Pharmaceuticals Ltd. |
| Address |
252, Dr. A.B. Road,
Worli
Mumbai
MAHARASHTRA
400030
India
Mumbai
MAHARASHTRA
400030
India |
| Phone |
91-22-2495395 |
| Fax |
91-22-24947415 |
| Email |
jeroze.j.dalal@gsk.com |
|
Details of Contact Person
Public Query
|
| Name |
Kedar Nayak |
| Designation |
Clinical Research Manager |
| Affiliation |
GlaxoSmithKline Pharmaceuticals Ltd. |
| Address |
252, Dr. A.B. Road,
Worli
Mumbai
MAHARASHTRA
400030
India
Mumbai
MAHARASHTRA
400030
India |
| Phone |
91-22-2495365 |
| Fax |
91-22-24947415 |
| Email |
kedar.n.nayak@gsk.com |
|
|
Source of Monetary or Material Support
|
| GlaxoSmithKline Pharmaceuticals Ltd. |
|
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Primary Sponsor
|
| Name |
GlaxoSmithKline Pharmaceuticals Ltd |
| Address |
GlaxoSmithKline Pharmaceuticals Ltd. 252, Dr. A.B. Road, Mumbai 400030. India. |
| Type of Sponsor |
Pharmaceutical industry-Global |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
Argentina
Austria
Belgium
China
Czech Republic
Denmark
Estonia
Finland
Germany
Greece
Hungary
India
Ireland
Israel
Japan
Netherlands
Norway
Poland
Republic of Korea
Russian Federation
Singapore
Spain
Sweden
Thailand
United Kingdom
United States of America |
|
Sites of Study
|
| No of Sites = 5 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Joseph John |
Christian Medical College |
Department of Hematology, Hemato oncology,Christian Medical College,Ludhiana - 141008 India.
Ludhiana
PUNJAB |
911615037957
911612606957
mjosephjohn@gmail.com |
| Dr Vikram Mathews |
Christian Medical College |
Department of Haematology,
Christian Medical College,
Vellore- 632004
Vellore
TAMIL NADU |
0416-2282352
0416-2226449
vikram@cmcvellore.ac.in |
| Dr Chetan Deshmukh |
Deenanath Mangeshkar Hospital & Research Center |
Deenanath Mangeshkar Hospital & Research Center, Erandawne, Pune – 411004
Maharashtra, India
Pune
MAHARASHTRA |
9850811449
drchetandeshmukh@gmail.com |
| Dr Vijay Ramanan |
Jehangir Clinical Development Centre Pvt Ltd. |
Jehangir Hospital Premises,
32 Sassoon Road, Pune 411001, Maharashtra, India
Pune
MAHARASHTRA |
020-67268800
020-26059319
mvijayr@gmail.com |
| Dr Bhausaheb Bagal |
Tata Memorial Centre |
Dept of Medical oncology,
Hematolymphoid – Adult,
Tata Memorial Centre,
Advanced Centre For Treatment, Research & Education in Cancer
Kharghar, Navi Mumbai – 410 210, Maharashtra, India
Mumbai
MAHARASHTRA |
9930428999
bagalbp@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 5 |
| Name of Committee |
Approval Status |
| Institutional Ethics Committee CMC Ludhiana |
Submittted/Under Review |
| Institutional Ethics committee, DMH & RC |
Submittted/Under Review |
| Institutional Review Board CMC Vellore |
Submittted/Under Review |
| Jehangir Clinical Development Center Institutional Review Board |
Approved |
| Tata Memorial Centre-ACTREC,IRB |
Submittted/Under Review |
|
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Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
Diffuse Large Cell B Cell Lymphoma or Grade 3b Follicular Lymphoma, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Ofatumumab |
Four infusions of ofatumumab will be administered as follows: Day 1 (or up to 3 days
prior to Day 1) and Day 8 (±2 days) of cycle 1 of the salvage chemotherapy cycle, and
then on Day 1 (or up to 3 days prior to Day 1) of cycles 2 and 3 of a 21 day cycle. The
Day 8 infusion may be delayed by up to 7 days if the subject experiences a grade ≥3 AE.
If the infusion cannot be dosed by Day 15 it should be omitted. The dose of ofatumumab
will be 1000mg and will be administered in an infusion volume of 1000mL |
| Comparator Agent |
Rituximab |
Rituximab will be administered, at a dose of 375mg/m2, on Day 1 (or up to 3 days prior
to Day 1) and Day 8 (±2 days) of cycle 1 of the salvage chemotherapy, and then on Day 1
(or up to 3 days prior to Day 1) of cycles 2 and 3 of a 21 day cycle. The Day 8 infusion
may be delayed by up to 7 days if the subject experiences a grade ≥3 AE. If the infusion
cannot be dosed by Day 15 it should be omitted. Refer to SPM for guidance on the
preparation of infusions and observations required during infusions. |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
55.00 Year(s) |
| Gender |
Both |
| Details |
1 CD20 positive DLBCL or grade 3b follicular lymphoma (FL) at original diagnosis If
a 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
Refractory disease must fulfill one of the following
continuing partial response (PR) from termination of first-line treatment The
lymphoma should 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 should 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
OR
1 clearly demarcated lesion/node with a long axis >2.0cm 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 |
|
| ExclusionCriteria |
| Details |
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
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 symptom
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) 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 |
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Centralized |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
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). |
Long Term Follow-up |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
To evaluate the following in subjects receiving O-chemo compared
to subjects receiving R-chemo:
• PFS in the DHAP subgroup |
Long Term Follow-up |
| Overall response rate after salvage chemoimmunotherapy |
3-Months Follow-up |
| Overall response rate three months after ASCT. |
3 Months Post ASCT Follow-up |
| Event-free survival. |
Long Term Follow-up |
| Overall survival. |
Long Term Follow-up |
Number of subjects with inadequate mobilisation of autologous stem cells (2.0
million CD34+ cells/kg) prior to administration of high dose therapy (HDT). |
HDT-ASCT Visit |
| Number of subjects completing ASCT. |
3 Months Post ASCT Follow-up |
| Changes in health-related quality of life (HRQL) measures. |
Long Term Follow-up |
Incidence, severity of adverse events, serious adverse events and other safety.
parameters. |
Long Term Follow-up |
Time to neutrophil and platelet recovery after each cycle of therapy including
HDT/ASCT. |
Long Term Follow-up |
|
|
Target Sample Size
|
Total Sample Size="380"
Sample Size from India="10"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 3 |
|
Date of First Enrollment (India)
|
20/07/2012 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
29/03/2010 |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="6"
Months="6"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Open to Recruitment |
| Recruitment Status of Trial (India) |
Other (Terminated) |
|
Publication Details
|
|
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Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
|
|
Brief Summary
|
This is a Phase III, parallel group, open label, active comparator, randomised (1:1),
intended registration trial of ofatumumab versus rituximab in addition to salvage
chemotherapy. Two salvage regimens, DHAP and DVD, will be included in the protocol.
HOVON centres will enter subjects into the DVD subgroup, all other centres will enter
subjects into the DHAP subgroup. Changes to this policy may be made subject to the
approval of the study management. Recruitment will continue until at least 280 subjects
are randomised into the DHAP subgroup. A maximum of 100 subjects will be recruited
into the DVD subgroup.
Subjects must be refractory to, or have relapsed following, first-line treatment with
rituximab in combination with an anthracycline- or anthracenedione- containing
chemotherapy regimen, and be eligible for ASCT. The following disease responses will
be deemed refractory: 1) progressive disease during first-line treatment, 2) stable disease
after at least 3 cycles of first-line treatment, and 3) PR after at least 6 cycles of first-line
treatment, or in the case of stage I/II disease at least 3 cycles of treatment and definitive
involved field radiotherapy. Subjects will be randomised to receive either rituximab or
ofatumumab in addition to salvage chemotherapy.
Ofatumumab or rituximab infusions will be administered on Day 1 and Day 8 of cycle 1,
and then on Day 1 of cycles 2 and 3. The dose of ofatumumab will be 1000mg and
rituximab will be administered at a dose of 375mg/m 2. Cycle 2 and 3 will be delayed for
hematological toxicity for a maximum of 2 weeks, thereafter the subject must be
withdrawn if neutrophil and platelet counts are not adequate for dosing.
Disease assessments, including CT and PET scans, will be performed at screening. After
the second cycle of salvage therapy, a CT scan will be performed and subjects not
achieving CR or PR will be considered treatment failures and will not receive any further
protocol therapy. According to local policy, during the second and/or third cycle of
salvage therapy, stem cells will be mobilized and harvested. CT and PET scans will be
performed after the third cycle of salvage therapy. Revised Response Criteria for
Malignant Lymphoma (RRCML) [ Cheson, 2007], modified as in Section 6.2.3, will be
used for disease assessment. Provided that subjects have CR, PR or SD, they will receive
high dose chemotherapy followed by autologous stem cell transplantation. Success of
engraftment will be assessed. Response will be assessed at 3 months post ASCT with CT
and PET scans.
From 9 months post-randomisation, subjects will be assessed every 3 months until two
years post randomisation, then every 6 months during years 3 and 4, and then at the end
of year 5. CT scans will be performed at 1 and 2 years post-randomisation or if clinically
indicated to exclude disease relapse.
Patient reported outcomes (PRO) will be collected using the FACT-Lym subscale,
FACT-G, EQ-5D and HCQ questionnaires at specified protocol visits. Paraffin blocks of
the original diagnostic biopsy and, when obtained, the biopsy following first-line
treatment will be submitted to central labs for pathological review and the production of
tissue microarrays (TMA) for subsequent prognostic marker analysis.
An interim analysis for futility of efficacy will be performed when 70 subjects in each
treatment group (O-chemo and R-chemo) have concluded salvage chemoimmunotherapy.
Adequacy of stem cell mobilization and safety will also be reviewed. If the results of the
interim analysis are satisfactory, the study will then complete recruitment Recruitment
will not be interrupted while the interim analysis is conducted. An IDMC will oversee the
conduct of the study. |