COALITION: 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)

Sponsor

Peter MacCallum Cancer Centre, Australia (Other)

Overall Status

Recruiting

CT.gov ID

NCT04914741

Collaborator

Hoffmann-La Roche (Industry)

Enrollment

Locations

Arms

48.1

Anticipated Duration (Months)

6.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B Cell Lymphoma High-grade B-cell Lymphoma	Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisolone Drug: Glofitamab Drug: Polatuzumab vedotin	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jun 29, 2021

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jul 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Glofitamab plus R-CHOP Participants will receive treatment in 21 day cycles consisting of R-CHOP in cycle 1, followed by R-CHOP plus glofitamab for cycles 2-6, and two cycles of glofitamab monotherapy consolidation. Patients may also receive high-dose methotrexate CNS prophylaxis at investigator discretion.	Drug: Rituximab Rituximab 375 mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Cyclophosphamide Cyclophosphamide 750mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Doxorubicin Doxorubicin 50mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Vincristine Vincristine 1.4mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Prednisolone Prednisolone 100mg orally on Days 1-5 of every 21-day cycle Drug: Glofitamab Glofitamab will be administered by IV infusion as per the schedule specified in the respective arm Other Names: RO7082859 CD20-TCB
Experimental: Glofitamab plus polatuzumab vedotin-RCHP Participants will receive treatment in 21 day cycles consisting of R-CHOP in cycle 1, followed by polatuzumab vedotin-RCHP plus glofitamab for cycles 2-6, and two cycles of glofitamab monotherapy consolidation. Patients may also receive high-dose methotrexate CNS prophylaxis at investigator discretion.	Drug: Rituximab Rituximab 375 mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Cyclophosphamide Cyclophosphamide 750mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Doxorubicin Doxorubicin 50mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle Drug: Prednisolone Prednisolone 100mg orally on Days 1-5 of every 21-day cycle Drug: Glofitamab Glofitamab will be administered by IV infusion as per the schedule specified in the respective arm Other Names: RO7082859 CD20-TCB Drug: Polatuzumab vedotin Polatuzumab 1.8mg/kg administered by IV infusion on Day 1 of every 21-day cycle

Arm

Intervention/Treatment

Experimental: Glofitamab plus R-CHOP

Participants will receive treatment in 21 day cycles consisting of R-CHOP in cycle 1, followed by R-CHOP plus glofitamab for cycles 2-6, and two cycles of glofitamab monotherapy consolidation. Patients may also receive high-dose methotrexate CNS prophylaxis at investigator discretion.

Drug: Rituximab

Rituximab 375 mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Cyclophosphamide

Cyclophosphamide 750mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Doxorubicin

Doxorubicin 50mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Vincristine

Vincristine 1.4mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Prednisolone

Prednisolone 100mg orally on Days 1-5 of every 21-day cycle

Drug: Glofitamab

Glofitamab will be administered by IV infusion as per the schedule specified in the respective arm

Other Names:

RO7082859

CD20-TCB

Experimental: Glofitamab plus polatuzumab vedotin-RCHP

Participants will receive treatment in 21 day cycles consisting of R-CHOP in cycle 1, followed by polatuzumab vedotin-RCHP plus glofitamab for cycles 2-6, and two cycles of glofitamab monotherapy consolidation. Patients may also receive high-dose methotrexate CNS prophylaxis at investigator discretion.

Drug: Rituximab

Rituximab 375 mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Cyclophosphamide

Cyclophosphamide 750mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Doxorubicin

Doxorubicin 50mg/m^2 administered by IV infusion on Day 1 of every 21-day cycle

Drug: Prednisolone

Prednisolone 100mg orally on Days 1-5 of every 21-day cycle

Drug: Glofitamab

Glofitamab will be administered by IV infusion as per the schedule specified in the respective arm

Other Names:

RO7082859

CD20-TCB

Drug: Polatuzumab vedotin

Polatuzumab 1.8mg/kg administered by IV infusion on Day 1 of every 21-day cycle

Outcome Measures

Primary Outcome Measures

To assess safety of the combination of glofitamab and R-CHOP or pola-RCHP according to number of participants with treatment-related adverse events [From start of treatment till the end of study, assessed up to approximately 60 months]
To evaluate the Relative Dose Intensity (RDI) of the chemotherapy backbone [From start of study treatment till the end of study treatment, assessed up to approximately 12 months]
To evaluate the rates of early chemotherapy discontinuation [From start of study treatment till the end of study treatment, assessed up to approximately 12 months]

Secondary Outcome Measures

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 [Up to approximately 6 months (each cycle is 21 days)]
To estimate overall response rate (ORR) [Up to approximately 6 months (each cycle is 21 days)]
To describe progression free survival (PFS) [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]
To describe the duration of response (DoR) measured in the subset of patients who achieved CR or PR [Time from the first documented disease response to the date of progressive disease or death, whichever occurs first, assessed up to approximately 60 months]
Overall survival (OS) as defined as the time from first dose of chemotherapy induction to the date of death from any cause [From first dose of chemotherapy induction to the date of death from any cause, assessed up to approximately 60 months]

Other Outcome Measures

Correlation between circulating tumour DNA detection and response (CR and ORR) [From start of treatment till end of study assessed up to 60 months]
Comparison of efficacy (rates of CR, ORR, DOR, PFS and OS) between the two study arms [From start of treatment till end of study assessed up to 60 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18yo and ≤65yo at the time of signing consent
Have a histologically confirmed diagnosis of one of the following, according to the 2016 WHO classification:
DLBCL, NOS or DLBCL arising as a result of transformation of an indolent lymphoma
HGBL, NOS
HGBL with rearrangements of MYC and BCL2 and/or BCL6
For DLBCL, and HGBL, NOS meets one of the following risk criteria:

NCCN-IPI of ≥4 or IPI ≥3 (appendix 1 and 3)

Considered fit for 6 cycles of full dose R-CHOP chemotherapy, as per the Investigator
ECOG performance status (appendix 5) of:
0-2 inclusive or 3 if directly attributable to lymphoma for patients entering the trial prior to cycle 1 of R-CHOP
0-1 inclusive for patients entering the trial at cycle 2
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)
Able to provide an archival pre-treatment biopsy.
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
Life expectancy (in the opinion of the Investigator) of ≥ 18 weeks
Adequate haematological function
Adequate renal function
Adequate hepatic function
Negative serologic or PCR test results for active acute or chronic HBV infection.
Non-haematological AEs from prior anti-cancer therapy must have resolved to Grade ≤1 (with the exception of alopecia and inclusion criteria 10-12)
Negative test results for HCV and HIV.

Exclusion Criteria:

Inability to comply with protocol mandated hospitalisations and restrictions
Prior systemic treatment of an underlying indolent lymphoma with an anthracycline-containing regimen
Richter's syndrome
Patients with known CNS involvement by lymphoma
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
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
Prior solid organ transplantation
Prior autologous or allogeneic stem cell transplantation
A history of treatment-emergent immune related AEs associated with prior immunotherapeutic agents
Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease
Note: patients with a history of stroke who have not experienced a stroke or transient ischaemic attack in the past 2 years are allowed
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
Past history of confirmed progressive multifocal leukoencephalopathy
Past history of chronic active EBV or HLH
Major surgery or significant traumatic injury <28 days prior to study treatment or anticipation of the need for major surgery during study treatment
Significant cardiovascular disease, defined as:
A left ventricular ejection fraction (as determined by nuclear gated blood pool scan or echocardiogram) <50%
Myocardial infarction or unstable angina within the past 6 months
Unstable arrhythmia
Any other cardiac illness that, in the opinion of the Investigator or CPI, makes the patient unsuitable for anthracycline containing therapy
Significant pulmonary disease, including but not limited to clinically significant obstructive pulmonary disease or history of bronchospasm
Current grade >1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease
Known clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
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
History of other active malignancy within 5 years prior to registration, with the exception of:
FL or MZL, previously untreated, or treated with no more than one line of therapy which must not have contained an anthracycline
Basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix
Prior malignancy treated with a curative intent that has remained in remission without treatment for ≥2 years prior to registration
Patients with known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) at registration

Note: Patients with latent tuberculosis are excluded

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
Major contraindication to any of the individual components of the chemotherapy backbone (R, C, H, O, Polatuzumab vedotin, prednisolone)
Patients who are pregnant or breastfeeding

Other protocol-defined inclusion and exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Concord Repatriation General Hospital	Camperdown	New South Wales	Australia	2050
2	St Vincent's Public Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
3	Calvary Mater Newcastle	Newcastle	New South Wales	Australia	2298
4	Prince of Wales Hospital	Randwick	New South Wales	Australia	2031
5	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
6	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
7	Barwon Health	Geelong	Victoria	Australia	3220
8	Cabrini Hospital	Malvern	Victoria	Australia	3144
9	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
10	St Vincent's Hospital Melbourne	Melbourne	Victoria	Australia	3065
11	Alfred Hospital	Melbourne	Victoria	Australia
12	Epworth Healthcare	Melbourne	Victoria	Australia
13	Sir Charles Gairdner Hospital	Nedlands	Western Australia	Australia	6009