Clinical trial NCT04914741: A Multicentre, Parallel Arm, Open-label Trial of Frontline R-CHOP/Pola-RCHP and Glofitamab in Younger, Higher Risk Patients With Diffuse Large B Cell Lymphoma (DLBCL)
Official title: A Multicentre Trial of Frontline R-CHOP/Pola-RCHP and Glofitamab in Younger, Higher Risk Patients With Diffuse Large B Cell Lymphoma (DLBCL)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Diffuse Large B Cell Lymphoma
High-grade B-cell Lymphoma
Keywords: DLBCL
HGBL
Lead sponsor: Peter MacCallum Cancer Centre, Australia
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2021-06-07
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open label, multi-centre, phase Ib/II, parallel arm study evaluating the safety and tolerability of glofitamab in addition to backbone chemotherapy consisting of R-CHOP or polatuzumab vedotin-RCHP for younger patients with higher-risk Diffuse Large B-cell Lymphoma or High Grade B-Cell Lymphoma.


Eligibility criteria: Inclusion Criteria:

1. Age ≥18yo and ≤65yo at the time of signing consent
2. Have a histologically confirmed diagnosis of one of the following, according to the 2016 WHO classification:

   1. DLBCL, NOS or DLBCL arising as a result of transformation of an indolent lymphoma
   2. HGBL, NOS
   3. HGBL with rearrangements of MYC and BCL2 and/or BCL6
3. For DLBCL, and HGBL, NOS meets one of the following risk criteria:

   a. NCCN-IPI of ≥4 or IPI ≥3 (appendix 1 and 3)
4. Considered fit for 6 cycles of full dose R-CHOP chemotherapy, as per the Investigator
5. ECOG performance status (appendix 5) of:

   1. 0-2 inclusive or 3 if directly attributable to lymphoma for patients entering the trial prior to cycle 1 of R-CHOP
   2. 0-1 inclusive for patients entering the trial at cycle 2
6. Patients must be treatment-naïve or have received a maximum of one cycle of full-dose R-CHOP chemotherapy (with or without a steroid pre-phase)
7. Able to provide an archival pre-treatment biopsy.
8. Have measurable disease on a pre-chemotherapy PET/CT, defined as at least one bi-dimensionally measurable nodal lesion of \>1.5cm in longest dimension, or at least one bi-dimensionally measurable extranodal lesion of \>1.0cm in longest dimension
9. Life expectancy (in the opinion of the Investigator) of ≥ 18 weeks
10. Adequate haematological function
11. Adequate renal function
12. Adequate hepatic function
13. Negative serologic or PCR test results for active acute or chronic HBV infection.
14. Non-haematological AEs from prior anti-cancer therapy must have resolved to Grade ≤1 (with the exception of alopecia and inclusion criteria 10-12)
15. Negative test results for HCV and HIV.

Exclusion Criteria:

1. Inability to comply with protocol mandated hospitalisations and restrictions
2. Prior systemic treatment of an underlying indolent lymphoma with an anthracycline-containing regimen
3. Richter's syndrome
4. Patients with known CNS involvement by lymphoma
5. With the exception of rituximab, any prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines, and monoclonal antibodies within 4 weeks or five half-lives of the drug, whichever is shorter, before the first dose of study drug
6. With the exception of CHOP used as a first cycle of lymphoma treatment, any chemotherapeutic agent, or treatment with any other investigational agent within 4 weeks prior to study treatment
7. Prior solid organ transplantation
8. Prior autologous or allogeneic stem cell transplantation
9. A history of treatment-emergent immune related AEs associated with prior immunotherapeutic agents
10. Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease

    1. Note: patients with a history of stroke who have not experienced a stroke or transient ischaemic attack in the past 2 years are allowed
    2. Note: patients with a history of epilepsy who have not experienced a seizure in the past 2 years are allowed, so long as continuation of any ongoing established pharmacologic treatment is not contraindicated
11. Past history of confirmed progressive multifocal leukoencephalopathy
12. Past history of chronic active EBV or HLH
13. Major surgery or significant traumatic injury \<28 days prior to study treatment or anticipation of the need for major surgery during study treatment
14. Significant cardiovascular disease, defined as:

    1. A left ventricular ejection fraction (as determined by nuclear gated blood pool scan or echocardiogram) \<50%
    2. Myocardial infarction or unstable angina within the past 6 months
    3. Unstable arrhythmia
    4. Any other cardiac illness that, in the opinion of the Investigator or CPI, makes the patient unsuitable for anthracycline containing therapy
15. Significant pulmonary disease, including but not limited to clinically significant obstructive pulmonary disease or history of bronchospasm
16. Current grade \>1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
17. Known clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
18. Administration of a live, attenuated vaccine within 4 weeks before study treatment note: influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine at any time during the study treatment period
19. History of other active malignancy within 5 years prior to registration, with the exception of:

    1. FL or MZL, previously untreated, or treated with no more than one line of therapy which must not have contained an anthracycline
    2. Basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix
    3. Prior malignancy treated with a curative intent that has remained in remission without treatment for ≥2 years prior to registration
20. Patients with known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) at registration

    a. Note: Patients with latent tuberculosis are excluded
21. Other significant life-threatening illness or medical condition which, in the Investigator's opinion, could compromise the patient's safety, interfere with absorption or metabolism of study drug, affect compliance with the protocol or interpretation of results, or put the study outcomes at undue risk
22. Major contraindication to any of the individual components of the chemotherapy backbone (R, C, H, O, Polatuzumab vedotin, prednisolone)
23. Patients who are pregnant or breastfeeding

Other protocol-defined inclusion and exclusion criteria may apply.

Primary outcomes:
measure: To assess safety of the combination of glofitamab and R-CHOP or pola-RCHP according to number of participants with treatment-related adverse events
timeFrame: From start of treatment till the end of study, assessed up to approximately 60 months
measure: To evaluate the Relative Dose Intensity (RDI) of the chemotherapy backbone
timeFrame: From start of study treatment till the end of study treatment, assessed up to approximately 12 months
measure: To evaluate the rates of early chemotherapy discontinuation
timeFrame: From start of study treatment till the end of study treatment, assessed up to approximately 12 months
Secondary outcomes:
measure: To estimate the proportion of patients achieving a complete response (CR) after cycles 2, 4 and at end of induction treatment (6 cycles) of the novel combination therapy according to Lugano 2014 criteria
timeFrame: Up to approximately 6 months (each cycle is 21 days)
measure: To estimate overall response rate (ORR)
timeFrame: Up to approximately 6 months (each cycle is 21 days)
measure: To describe progression free survival (PFS)
timeFrame: From first dose of chemotherapy induction to first date of objectively documented progressive disease or date of death of any cause, whichever occurs first, assessed up to approximately 60 months
measure: To describe the duration of response (DoR) measured in the subset of patients who achieved CR or PR
timeFrame: Time from the first documented disease response to the date of progressive disease or death, whichever occurs first, assessed up to approximately 60 months
measure: Overall survival (OS) as defined as the time from first dose of chemotherapy induction to the date of death from any cause
timeFrame: From first dose of chemotherapy induction to the date of death from any cause, assessed up to approximately 60 months
Other outcomes:
measure: Correlation between circulating tumour DNA detection and response (CR and ORR)
timeFrame: From start of treatment till end of study assessed up to 60 months
measure: Comparison of efficacy (rates of CR, ORR, DOR, PFS and OS) between the two study arms
timeFrame: From start of treatment till end of study assessed up to 60 months
Locations:
city: Camperdown
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Public Hospital Sydney
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexander Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Geelong
country: Australia
facility: Barwon Health
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Epworth Healthcare
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
Study officials:
affiliation: Peter MacCallum Cancer Centre & Royal Melbourne Hospital
name: Michael Dickinson
role: PRINCIPAL_INVESTIGATOR
References: