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Trial registered on ANZCTR


Registration number
ACTRN12623000620628
Ethics application status
Approved
Date submitted
17/03/2023
Date registered
6/06/2023
Date last updated
11/08/2024
Date data sharing statement initially provided
6/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
NHL38 Epco-Sandwich: A trial to assess the safety and efficacy of Epcoritamab-containing combination salvage therapy followed by autologous stem cell transplantation and Epcoritamab consolidation in patients with relapsed large B-cell lymphoma.
Scientific title
NHL38 Epco-Sandwich: A phase II multicentre, single arm, open-label trial of epcoritamab-containing combination salvage therapy followed by autologous stem cell transplantation and epcoritamab consolidation in patients with relapsed large B-cell lymphoma.
Secondary ID [1] 309216 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diffuse Large B-Cell Lymphoma 329372 0
Condition category
Condition code
Cancer 326315 326315 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Epcoritamab:
1)Epcoritamab-Salvage treatment: 2-3 cycles of R-DHAOx therapy (rituximab, dexamethasone, cytarabine, oxaliplatin), given every 21 days combined with Epcoritamab subcutaneous weekly dosing (priming 0.16mg Cycle1 Day1 (C1D1), intermediate 0.8mg C1D8, full dose 48mg from C1D15 onwards)
•Dosing regimen for R-DHAOx is as follows for each 21-day cycle:
- Rituximab 375mg per m2 intravenous infusion Day 1
- Dexamethasone 40mg oral Days 1 to 4
- Oxaliplatin 130mg per m2 intravenous infusion Day 1
- Cytarabine 2000mg per m2 intravenous infusion Days 2 and 3
•Patients who achieve a complete response after cycle 2 of Epcoritamab-chemotherapy salvage may receive an optional third cycle of Epcoritamab-salvage and proceed to transplant.
•Patients who achieve a partial response may: receive a third cycle of Epcoritamab-chemotherapy salvage and proceed to transplant or cease study treatment and switch to an alternative therapy
•Patients with progressive disease will cease study treatment and continue in survival follow-up

2) Autologous Stem Cell Transplant (ASCT) - Stem cell collection to occur following 2nd or 3rd cycle of salvage. This consists of BCNU (Carmustine), etoposide, cytarabine and melphalan (BEAM) conditioning chemotherapy followed by autologous stem cell reinfusion

3) Consolidation treatment: 6 cycles (28 days each) of subcutaneous Epcoritamab, commencing between 6-12 weeks post ASCT.
Epcoritamab dosing and timing for consolidation:
• Cycle 1 Day 1: Priming (0.16mg) dose
• Cycle 1 Day 8: intermediate (0.8mg) dose
• Cycle 1 Day 15: full dose 48mg
• Cycle 1 Day 22, Cycle 2-3 Days 1, 8, 15 and 22: 48mg
• Cycles 4 to 6 – Days 1 and 15 (fortnightly dosing): 48mg


4) Epcoritamab re-treatment: Epcoritamab re-treatment may be initiated for patients who achieve a complete response to protocol therapy and subsequently relapse. Re-treatment will continue until disease progression, or the patient fulfills the criteria for discontinuation. Dosing is as per above consolidation treatment.
Epcoritamab dosing and timing for re-treatment:
• Cycle 1 Day 1: Priming (0.16mg) dose
• Cycle 1 Day 8: intermediate (0.8mg) dose
• Cycle 1 Day 15: full dose 48mg
• Cycle 1 Day 22. Cycle 2 Days 1, 8, 15 and 22: 48mg
• Cycles 3 to 6 – Days 1 and 15 (fortnightly dosing): 48mg
• Cycles 7 and onwards – Day 1: 48mg

Tocilizumab:
Tocilizumab is available as a liquid concentrate for Intra-venous (IV) infusion. Each vial contains 200mg/10mL concentrate solution. Tocilizumab will be used in patients who have Cytokine Release Syndrome (CRS) then receive antipyretic or anticytokine therapy such as tocilizumab.
Tocilizumab should be administered at a dose of 8 mg/kg IV (8 mg/kg for patients at or above 30-kg weight only; 12 mg/kg for patients less than 30 kg weight; doses exceeding 800 mg per infusion are not recommended); repeat every 8 hours as necessary (up to a maximum of 4 doses).


All patients can continue to the subsequent phases of Epcoritamab treatment as scheduled until one of the following criteria applies:
• Disease progression at any time,
• Stable disease after cycle 2 (C2) of salvage treatment,
• Partial response after C2 of salvage treatment and physician decision to change therapy,
• Intercurrent illness that prevents further administration of treatment,
• Unacceptable Adverse Events (AEs)
• Patient decides to withdraw from treatment or the study, or
• General or specific changes in the patient’s condition render the patient unacceptable for further treatment in the opinion of the investigator.
• Major protocol violation or deviation of the protocol that is incompatible with ongoing participation
• Use of a prohibited therapy deemed by the CI to preclude ongoing study participation (e.g. use of a new anti-lymphoma therapy)
• Pregnancy of a female subject

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.

Participants who do not require Epcoritamab re-treatment should complete all treatments approximately 10-12 months post-enrolment (salvage ~ 1.5mths, ASCT ~3 months, consolidation 6 months)
Intervention code [1] 325666 0
Treatment: Drugs
Intervention code [2] 325730 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334177 0
To evaluate clinical efficacy of combination Epcoritamab with salvage-ASCT, according to Lugano criteria for response assessment (based on CT or PET-CT response).
Timepoint [1] 334177 0
Event-free survival (EFS) at 12 months and time to event outcome (measured in days) from registration to date of first to occur out of reduced partial response (PR) after cycle 2, commencement of non-protocolised cancer treatment, progression or death from any cause.

Event-free survival (EFS) at 12 months and time to event outcome (measured in days) from date of ASCT to date of first to occur out of reduced partial response (PR) after cycle 2, commencement of non-protocolised cancer treatment, progression or death from any cause.

Event-free survival (EFS) at 12 months and time to event outcome (measured in days) from commencement of Epcoritamab re-treatment to date of first to occur out of reduced partial response (PR) after cycle 2, commencement of non-protocolised cancer treatment, progression or death from any cause.

These will be assessed as a composite primary outcome.
Secondary outcome [1] 419653 0
To evaluate safety and tolerability of combination Epcoritamab with salvage-ASCT
Timepoint [1] 419653 0
Rate of adverse events according to CTCAE criteria v 6.0 expressed as a number and proportion. Adverse event assessment will be performed from enrolment, during cycles 1-3 of salvage treatment, during ASCT, cycles 1-6 during Consolidation, 12 months from registration and 30 days after the final treatment is completed.
Secondary outcome [2] 419654 0
Overall response rate (ORR)
Timepoint [2] 419654 0
Defined as achievement of at least a partial response to treatment according to Lugano criteria for response assessment (based on CT or PET-CT response). i.e. achievement of a PR or Complete Remission (CR) at any time during study participation
Secondary outcome [3] 419655 0
Complete response rate (CRR)
Timepoint [3] 419655 0
defined as achievement of CR at any time during study according to Lugano criteria for response assessment (based on CT or PET-CT response).
Secondary outcome [4] 419656 0
Overall Survival (OS)
Timepoint [4] 419656 0
Defined as the time from commencement of study treatment until death from any cause.
Secondary outcome [5] 419657 0
Progression free survival (PFS)
Timepoint [5] 419657 0
Defined as the time from commencement of study treatment until disease progression or death from any cause, following Epcoritamab-chemotherapy salvage, transplant and maintenance. Time to event outcome is measured in days. Measures to assess this outcome are haematology, biochemistry, PET/CT, physical examination, neurological examination, ECOG performance, ECG, haematology, biochemistry and assessment of survival.
These will be assessed as a composite secondary outcome.

Eligibility
Key inclusion criteria
1. Age 18 years or older
2. Confirmed diagnosis of DLBCL, Not-otherwise specified (NOS), Transformation of indolent B-cell lymphoma, High-grade B-cell lymphoma (HGBCL), NOS, Diffuse-large BCL (DLBCL)/HGBL with MYC and BCL2 rearrangements or Follicular large B-cell lymphoma according to WHO 2016 or 2022 criteria that has relapsed or progressed after one line of chemoimmunotherapy
3. Transplant eligible according to local assessment
4. ECOG performance status 0-2
5. Measurable disease on CT scan, defined as a nodal site greater than 1.5cm in longest axis or an extranodal site greater than 1.0cm in longest axis AND baseline fluorodeoxyglucose (FDG) positron emission tomography (PET) scans must demonstrate positive lesion compatible with CT defined anatomical tumour sites
6. Histological confirmation of tumour CD20 positivity, analysed by immunohistochemistry, on a pre-enrolment tissue sample performed after most recent prior therapy
7. Adequate renal function
- Creatinine clearance greater than 45mL per min (Cockcroft Gault formula)
8. Adequate hepatic function:
- Aspartate transaminase (AST) and alanine transaminase (ALT) less than or equal to 3x Upper Limit of Normal (ULN)
- Bilirubin less than or equal to 1.5xULN or less than or equal to 3 if documented liver involvement and/or Gilbert’s disease.
9. Adequate haematologic function:
- Haemoglobin greater than or equal to 90g/L (transfusion support permitted)
- Absolute neutrophil count greater than or equal to 1.0 x 109 per L; growth factor support allowed in case of bone marrow involvement
- Platelet count greater than 75 x 109 per L or greater than or equal to 50 x 109 per L if documented marrow involvement
10. Able to take oral medications
11. Adequate washout of prior therapies:
- At least 4 weeks since last dose of immunochemotherapy, radio-conjugated or toxin-conjugated compound, or other investigational anti-cancer therapy
- At least 6 weeks since chimeric antigen-receptor T-cell therapy
12. Resolution of toxicities from prior therapy to a grade that does not contraindicate trial participation in the opinion of the investigator
13. If receiving glucocorticoid treatment at screening, treatment must be tapered down and administered with a maximum of 25 mg daily in the last 14 days before the first dose of Epcoritamab
14. Before the first dose of Epcoritamab, during the trial and for 12 months after last administration of Epcoritamab, a woman must be either:
a. Not of childbearing potential, defined as: premenarchal; postmenopausal (greater than 45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone [FSH] level greater than 40 IU per L or mIU per mL); permanently sterilized (e.g., bilateral tubal occlusion [which includes tubal ligation procedures as consistent with local regulations], hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy
b. Of childbearing potential and practicing a highly effective method of birth control (as defined by the EU Clinical Trial Facilitation Group) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials: e.g., established use of oral, injected or implanted combined (estradiol and progesterone containing) hormonal contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); male partner sterilization (the vasectomized partner should be the sole partner for that patient); true abstinence (when this is in line with the preferred and usual lifestyle of the patient)
* If the childbearing potential changes after start of the trial (e.g., woman who is not heterosexually active becomes active, premenarchal woman experiences menarche) a woman must begin a highly effective method of birth control, as described under 16b
15. A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control (that is the use of condom) during the trial and for 12 months after receiving the last dose of Epcoritamab
16. Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for 12 months after receiving the last dose of Epcoritamab. Men must also not donate sperm during the trial and for 12 months after receiving the last dose of Epcoritamab
17. The patient understands the purpose of the trial and procedures required for the trial and is capable of giving signed informed consent which includes compliance with the requirements (no medical or psychiatric reason precluding participation) and restrictions listed in the informed consent form (ICF) and in this protocol
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Diagnosis of primary Central Nervous System (CNS) lymphoma
2. Active secondary CNS involvement of lymphoma at time of screening
- A prior history of secondary CNS lymphoma is allowed provided that it has been successfully treated and there are no features of recurrence.
3. Prior autologous stem cell transplant
4. Known past or current malignancy other than inclusion diagnosis, except for:
a. Cervical carcinoma of Stage 1B or less.
b. Non-invasive basal cell or squamous cell skin carcinoma.
c. Non-invasive, superficial bladder cancer.
d. Prostate cancer with a current Prostate Specific Agent (PSA) level less than 0.1 ng per mL
e. Indolent lymphoma
f. Other malignancy that has been treated with curative intent and has remained in remission for 2 years
5. Any prior therapy with a bispecific antibody targeting CD3 and CD20
6. Uncontrolled systemic infection
7. Known HIV infection
8. Known active hepatitis B or C infection based on criteria below:
- Hepatitis B virus (HBV): Patients with positive HbsAg are excluded. Patients with positive hepatitis B core antibody (antiHBc) and negative HbsAg require negative hepatitis B polymerase chain reaction (PCR) before enrolment and must be treated with antiviral therapy. Patients who are hepatitis B PCR positive will be excluded.
- Hepatitis C virus (HCV): If positive hepatitis C antibody, patient will need to have a negative hepatitis C ribonucleic acid (RNA) before enrolment. Patients who are hepatitis C RNA positive will be excluded.
9. Seizure disorder, unless seizure-free for 12 months on established anticonvulsant therapy without the requirement for modification to anticonvulsants within the prior 12 months
10. Known clinically significant cardiac disease, including:
a. Onset of unstable angina pectoris within 6 months of signing the patient informed consent form (PICF)
b. Acute myocardial infarction within 6 months of signing the PICF
c. Congestive heart failure (grade III or IV as classified by the New York Heart Association
d. Decreased ejection fraction of less than 45%
11. Confirmed history or current autoimmune disease requiring permanent immunosuppressive therapy. Low-dose prednisolone (less than or equal to 10mg/day or equivalent) for rheumatoid arthritis or similar conditions is allowed.
12. Exposed to live or live attenuated vaccine within 4 weeks prior to signing PICF
13. Women who are pregnant or lactating.
14. Patient has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments
15. Known hypersensitivity or adverse reaction to rituximab, tocilizumab or any elements of DHAOx
16. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. This condition must be discussed with the patient prior to signing consent and registration in the trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/08/2024
Actual
27/05/2024
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
39
Accrual to date
7
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 26928 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 26929 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 26930 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [4] 26931 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [5] 26932 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [6] 26933 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [7] 26934 0
The Canberra Hospital - Garran
Recruitment hospital [8] 26935 0
Concord Repatriation Hospital - Concord
Recruitment hospital [9] 26936 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 43000 0
3000 - Melbourne
Recruitment postcode(s) [2] 43001 0
5000 - Adelaide
Recruitment postcode(s) [3] 43002 0
3220 - Geelong
Recruitment postcode(s) [4] 43003 0
2065 - St Leonards
Recruitment postcode(s) [5] 43004 0
4029 - Herston
Recruitment postcode(s) [6] 43005 0
3168 - Clayton
Recruitment postcode(s) [7] 43006 0
2605 - Garran
Recruitment postcode(s) [8] 43007 0
2139 - Concord
Recruitment postcode(s) [9] 43008 0
7000 - Hobart
Recruitment outside Australia
Country [1] 25328 0
New Zealand
State/province [1] 25328 0

Funding & Sponsors
Funding source category [1] 313405 0
Other Collaborative groups
Name [1] 313405 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Country [1] 313405 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
ALLG Ground floor, 35 Elizabeth St Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 315178 0
None
Name [1] 315178 0
Address [1] 315178 0
Country [1] 315178 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312622 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 312622 0
305 Grattan St, Melbourne VIC 3000
Ethics committee country [1] 312622 0
Australia
Date submitted for ethics approval [1] 312622 0
10/07/2023
Approval date [1] 312622 0
11/12/2023
Ethics approval number [1] 312622 0

Summary
Brief summary
The purpose of this study is to evaluate clinical efficacy of incorporating Epcoritamab into the salvage regimen for relapsed-refractory aggressive B-cell lymphoma, followed by autologous stem-cell transplantation (ASCT) and consolidation Epcoritamab.

Who is it for?
You may be eligible for this study if you are aged 18 and above and are transplant-eligible with diffuse large B cell lymphoma that has relapsed or progressed after at least one line of immunochemotherapy.

Study details
This study design involves phases for Epcoritamab-Salvage treatment, ASCT and Consolidation treatment.
1. Epcoritamab-Salvage treatment:
Salvage treatment consists of 3 cycles of R-DHAOx (rituximab, dexamethasone, cytarabine, oxaliplatin) plus Epcoritamab, given in 21 day cycles. Epcoritamab is commenced in cycle 1, consisting of weekly dosing on days 1, 8 and 15, three doses per cycle. Priming (0.16mg) on C1D1 and intermediate (0.8mg) C1D8 dosing will be administered prior to full dose (48mg) on C1D15 and ongoing.
Response assessment will be performed after 2 cycles of Epcoritamab-salvage according to Lugano Criteria 2014.
• Patients who achieve complete remission (CR) may proceed directly to ASCT or may receive 1 further cycle of combination Epco-R-DHAOx and then proceed to ASCT.
• Patients who achieve partial response (PR) will receive 1 further cycle of combination Epco-R-DHAOx and proceed to ASCT or may cease protocolised therapy based on physician choice and enter the Post Treatment follow up phase.
• Patients achieving less than PR will not receive further protocol therapy and will enter overall survival (OS) follow up.

2. Autologous stem cell transplant:
Stem cell collection will occur following either the second or third cycle of salvage Epcoritamab as per institutional policies. Stem cell recollection is allowed in the event of unsuccessful first collection.
Pre-autograft eligibility assessment for ASCT will be performed according to local practice. ASCT may be administered at local referring centre and will follow local standard operative procedures.
• Note: Patients who respond to salvage-Epcoritamab treatment but are not considered eligible for the transplant procedure for reasons other than insufficient response (e.g. due to toxicity or failed stem cell mobilisation) may proceed directly to the Consolidation Phase instead of proceeding to ASCT
BEAM chemotherapy will be used for conditioning as per institutional guidelines.

3. Consolidation treatment:
Consolidation treatment consists of six 28-day cycles of subcutaneous Epcoritamab, commencing between 6 and 12 weeks post ASCT.

Other testing that will be performed includes physical examination, neurological examination, ECOG performance, ECG, haematology, biochemistry and monitoring of adverse events.

It is hoped this research will prove the safety of Epcoritamab in this “sandwich” design with ASCT in relapsed-refractory aggressive B-cell lymphoma
Trial website
Trial related presentations / publications
Public notes
NHL - Non-Hodgkin's Lymphoma

Contacts
Principal investigator
Name 125318 0
Prof Michael Dickinson
Address 125318 0
Peter MacCallum Cancer Centre 305 Grattan Street Melbourne VIC 3000
Country 125318 0
Australia
Phone 125318 0
+61 3 8559 5000
Fax 125318 0
Email 125318 0
[email protected]
Contact person for public queries
Name 125319 0
Delaine Smith
Address 125319 0
Australasian Leukaemia & Lymphoma Group, 35 Elizabeth St, Richmond VIC 3121
Country 125319 0
Australia
Phone 125319 0
+61 03 8373 9701
Fax 125319 0
Email 125319 0
[email protected]
Contact person for scientific queries
Name 125320 0
Delaine Smith
Address 125320 0
Australasian Leukaemia & Lymphoma Group, 35 Elizabeth St, Richmond VIC 3121
Country 125320 0
Australia
Phone 125320 0
+61 03 8373 9701
Fax 125320 0
Email 125320 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified IPD data for all data collected during the trial
When will data be available (start and end dates)?
Data available 3 months following publication, for an indefinite period
Available to whom?
Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted.
Available for what types of analyses?
Any type of analysis
Assessed on a case-by-case basis
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
20184Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]



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