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Trial registered on ANZCTR


Registration number
ACTRN12622001275752p
Ethics application status
Not yet submitted
Date submitted
7/09/2022
Date registered
28/09/2022
Date last updated
28/09/2022
Date data sharing statement initially provided
28/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
NHL37 - A phase I/II study to assess safety of combining Glofitamab and Pirtobrutinib (LOXo-305) for treatment in patients with Mantle Cell Lymphoma (MCL) and prior therapy with a BTK inhibitor.
Scientific title
NHL37 - An open-label, single-arm, phase 1-2 trial of GlOfitamab anD pIrtobrutinib (LOXo-305) in patients with mantle cell lymphoma and prior exposure to a BTK inhibitor
Secondary ID [1] 307877 0
ALLG - NHL37 (GOlDiLOX)
Universal Trial Number (UTN)
Trial acronym
GOlDiLOX
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Mantle Cell Lymphoma 327513 0
Condition category
Condition code
Cancer 324623 324623 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study design involves phases for treatment ramp-up, fixed course combination and maintenance.

Pirtobrutinib will be administered by oral tablet at a dosage of 200mg/day for the duration of all phases in this study. In addition, the following treatment regimen will be followed.

Treatment Ramp Up
1. Pre-Phase (7 days): 1000mg of Obinutuzumab administered intravenously (IV) on day 7 and a second dose administered between Day 6 and Day 1
2. Cycle 1: An initial dose level of Glofitamab will evaluate step-up dosing. If excessive dose-limiting toxicity is observed, including cytokine release syndrome (CRS), a lower initial dose of 1.25mg of glofitamab will be evaluated at "dose level -1".
Dose level 1 (14 days):
*2.5mg Glofitamab by IV on Day 1
*10mg Glofitamab by IV on Day 8
Dose level -1 (21 days):
*1.25mg Glofitamab by IV on Day 2
*2.5mg Glofitamab by IV on Day 8
*10mg Glofitamab by IV on Day 15
3. Cycle 2 (21 days): 30mg Glofitamab by IV on Day 1

Fixed course combination phase
Cycles 3-12 (21 days per cycle): 30mg of Glofitamab by IV on day 1

Maintenance phase
Cycle 13+ (28 days per cycle): Glofitamab discontinued. Pirtobrutinib 200mg oral daily. Maintenance treatment is planned to continue indefinitely until participants permanently cease study medications for any reason (eg. toxicity, disease progression), followed by End of Treatment assessments and safety follow ups.

Patients will only move on to the next consecutive phase once the previous phase is completed. All treatment will be administered by the study team.
Intervention code [1] 324345 0
Treatment: Drugs
Comparator / control treatment
N/A
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332442 0
To evaluate the efficacy of combination Pirtobrutinib and Glofitmab in patients with relapsed/refractory MCL and prior BTK inhibitor exposure.
Timepoint [1] 332442 0
Determined by the complete response (CR) rate according to Lugano criteria following 6 cycles (or approximately 18 weeks) following first treatment
Secondary outcome [1] 413512 0
Complete response rate using the Lugano Criteria for response assessment
Timepoint [1] 413512 0
At end of 12 cycles of Glofitamab
Secondary outcome [2] 413513 0
Assessment of adverse events (eg. fatigue, diarrhoea, confusion, nausea, constipation, anaemia, dyspnoea)
Timepoint [2] 413513 0
Incidence, nature and severity of adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Performed at every visit during the study, end of treatment and at safety follow up (30 days after EOT).
Secondary outcome [3] 413514 0
Overall response rates (complete or partial response) to combination therapy.
Timepoint [3] 413514 0
Using the Lugano criteria at the end of combination therapy (cycle 12)
Secondary outcome [4] 413515 0
Overall response rates
Timepoint [4] 413515 0
Using the Lugano criteria at end of Glofitamab induction.
Secondary outcome [5] 413516 0
Absence of minimal residual disease (MRD)
Timepoint [5] 413516 0
Measured by aggregate measure of peripheral blood and/or bone marrow flow cytometry, PCR and ctDNA following six cycles and at end of combination treatment
Secondary outcome [6] 413517 0
Progression-free survival (PFS)
Timepoint [6] 413517 0
Determined based on the modified Lugano criteria. Progression is measured from the date of registration to the date of first progression at any site or date of death due to any cause. Patients alive and progression-free at the last efficacy follow-up visit will be censored at the visit date.
Secondary outcome [7] 413518 0
Duration of response
Timepoint [7] 413518 0
Assessed using the Lugano criteria. Defined as the time from the first occurrence of a documented response (CR or PR) to the date of progression or death from any cause,
Secondary outcome [8] 413519 0
Overall survival (OS)
Timepoint [8] 413519 0
Defined as the time from registration to date of death from any cause. Patients who have not died by the study close-out date will be censored at their last visit. Patients who are lost to follow-up before the close-out date and who are not known to have died will be censored at the date they were last known to be alive

Eligibility
Key inclusion criteria
1. Ages 18 years old or above
2. A confirmed diagnosis of MCL according to World Health Organization (2016) criteria
3. At least one site of measurable disease not previously irradiated (defined as at least one bi-dimensionally measurable nodal lesion of greater than or equal to 1.5cm in longest dimension)
4. Life expectancy (in the opinion of the investigator) of greater than or equal to 18 weeks
5. Prior therapy with a BTK inhibitor alone or in combination and:
a. Progression or relapse post BTK inhibitor or
b. Failed to achieve PR following 12 weeks of BTK inhibitor therapy
6. Prior TRAEs must have recovered to Grade 1 or less with the exception of alopecia, peripheral neuropathy and lymphopenia.
7. ECOG 0-2
8. Adequate washout of prior therapies:
a. Broad field radiation (greater than or equal to 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study treatment
b. Palliative limited field radiation must be completed 7 days prior to study treatment.
c. Targeted agents, investigational agents, therapeutic monoclonal antibodies/antibody drug conjugates or cytotoxic chemotherapy must be completed 5 half-lives or 2 weeks (whichever is shorter) prior to study treatment (except for BTK inhibitors which may be continued until 1 day prior to planned first therapy with pirtobrutinib)
d. Steroids (prednisolone less than or equal to 100mg daily or equivalent for up to 14 days are permitted during screening for control of lymphoma related symptoms
9. Ability to take oral medications
10. Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.
11. Willingness of men and women of reproductive potential to observe conventional and highly effective and acceptable birth control methods for the duration of treatment and for six months following the last dose of study treatment
12. Women of childbearing potential must have a negative serum pregnancy test within seven days of enrolment
13. Adequate coagulation, defined as aPTT and PT not greater than 1.5xULN, unless laboratory abnormality is explained by concomitant anticoagulant medication, a lupus anticoagulant, or a factor deficiency not associated with an increased bleeding risk, as determined by the investigator.
14. Adequate liver function:
-ALT and AST less than or equal to 3X ULN, or less than or equal to 5X ULN if documented liver involvement
-Total bilirubin less than or equal to 1.5X ULN or less than or equal to 5X ULN if documented liver involvement and/or Gilbert’s Disease
15. Adequate renal function
- Creatinine clearance greater than or equal to 30mls/minute according to Cockroft-Gault formula
16. Adequate haematological parameters
- Haemoglobin greater than or equal to 80g/L (transfusion support permitted)
- Absolute neutrophil count greater than or equal to 1.0x10^9/L (May be G-CSF supported)
- Platelets greater than or equal to 75 X 10^9/L. OR platelets greater than or equal to 50 X 10^9/L if documented marrow involvement or splenomegaly (must be platelet transfusion independent for 7 days prior to first dose of obinutuzumab
17. Sufficient archival tissue is available for central review or after discussion with the CPI
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to comply with protocol mandated hospitalisations
2. For patients enrolling on the safety cohort, a history of allogeneic transplantation within 12 months of enrolment or ongoing chronic GVHD or immunosuppressive therapy.
3. Autologous SCT or CAR-T therapy within 6 weeks of enrolment
4. Active central nervous system involvement with MCL
5. Prior treatment with pirtobrutinib or demonstrated refractoriness to a CD20xCD3 bispecific antibody.
6. Have a known severe hypersensitivity to any of the excipients of pirtobrutinib, glofitamab, tocilizumab or obinutuzumab.
7. History of stroke or intracranial haemorrhage within six months of enrolment.
8. Live vaccination within 28 days of enrolment.
9. Major surgery or significant traumatic injury within 28 days of study treatment or the anticipation of major surgery during study treatment (surgical procedures for the diagnosis of lymphoma such as lymph node resection/ laparoscopy are allowed provided patient is considered fit for treatment as judged by investigator)
10. Significant cardiovascular disease defined as:
a. Unstable angina or acute coronary syndrome within 2 months of registration
b. History of myocardial infarction within 3 months prior to registration
c. Documented LVEF by any method of = 40% during screening
d. Grade 3 or higher NYHA functional classification system of heart failure
e. Uncontrolled or symptomatic arrhythmias
11. Prolongation of the QT interval corrected for heart rate (QTcF) greater than 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF greater than 470 msec on all 3 ECGs, during Screening. QTcF is calculated using Fridericia’s Formula (QTcF): QTcF euqal to QT/(RR0.33)
Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switching to another drug not known to be associated with QTcF prolongation. Correction for underlying bundle branch block (BBB) allowed. Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias
12. Known human immunodeficiency virus (HIV) infection
13. Known active HBV or HCV infection based on criteria below:
a. HBV: Patients with positive HbsAg are excluded. Patients with positive hepatitis B core antibody antiHBc and negative HbsAg require negative hepatitis B PCR before enrolment and must be treated with antiviral therapy. Patients who are hepatitis B PCR positive will be excluded.
b. HCV: If positive hepatitis C antibody, patient will need to have a negative hepatitis C RNA before enrolment. Patients who are hepatitis C RNA positive will be excluded.
14. Known active CMV infection. Unknown or negative status are eligible.
15. Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment.
16. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of pirtobrutinib.
17. Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection, or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation.
18. Active uncontrolled auto-immune cytopenia (e.g., AIHA, ITP) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrolment to maintain adequate blood counts, unless auto-immune cytopenias are secondary to MCL
19. Active second malignancy unless in remission and with life expectancy greater than 2 years.
20. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and/or strong P-gp inhibitors.
21. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/05/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 24991 0
New Zealand
State/province [1] 24991 0

Funding & Sponsors
Funding source category [1] 312150 0
Other Collaborative groups
Name [1] 312150 0
Australasian Leukaemia and Lymphoma Group
Country [1] 312150 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] 313685 0
None
Name [1] 313685 0
None
Address [1] 313685 0
None
Country [1] 313685 0
Other collaborator category [1] 282421 0
Individual
Name [1] 282421 0
Michael Dickinson (Co-Principal Investigator)
Address [1] 282421 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country [1] 282421 0
Australia

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 311543 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 311543 0
305 Grattan Street
Melbourne VIC 3000
Ethics committee country [1] 311543 0
Australia
Date submitted for ethics approval [1] 311543 0
14/11/2022
Approval date [1] 311543 0
Ethics approval number [1] 311543 0

Summary
Brief summary
The purpose of this study is to evaluate the safety and efficacy of combination pirtobrutinib and glofitmab in patients with relapsed/refractory MCL and prior BTK inhibitor exposure.

Who is this study for?
You may be eligible to join this study if you are aged 18 or over and have been diagnosed with relapsed/refractory MCL.

Study details:
This study design involves phases for treatment ramp-up, fixed course combination and maintenance.

Treatment Ramp Up
1. Pre-Phase (7 days): Pirtobrutinib 200mg oral daily. 1000mg of Obinutuzumab administered intravenously (IV) on D-7 and a second dose administered between Day 6 and Day 1
2. Cycle 1: Pirtobrutinib 200mg oral daily. An initial dose level of Glofitamab will evaluate step-up dosing. If excessive dose-limiting toxicity is observed, including cytokine release syndrome (CRS), a lower initial dose of 1.25mg of glofitamab will be evaluated at "dose level -1".
Dose level 1 (14 days):
*Pirtobrutinib 200mg oral daily
*2.5mg Glofitamab by IV on Day 1
*10mg Glofitamab by IV on Day 8
Dose level -1 (21 days):
*Pirtobrutinib 200mg oral daily
*1.25mg Glofitamab by IV on Day 2
*2.5mg Glofitamab by IV on Day 8
*10mg Glofitamab by IV on Day 15
3. Cycle 2 (21 days): 30mg Glofitamab by IV on Day 1

Fixed course combination phase
Cycles 3-12 (21 days per cycle): Pirtobrutinib 200mg oral daily, 30mg of Glofitamab by IV on day 1.

Maintenance phase
Cycles 13+ (28 days per cycle): Pirtobrutinib 200mg oral daily. Glofitamab discontinued.

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

It is hoped that this study will provide evidence for the safety of pirtobrutinib and glofitmab used in combination for relapsed/refractory MCL patients.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121478 0
A/Prof Chan Cheah
Address 121478 0
Sir Charles Gairdner Hospital
85 Monash Avenue
Hollywood Medical Centre
Nedlands, WA, 6009
Country 121478 0
Australia
Phone 121478 0
+61 08 6119 4457
Fax 121478 0
Email 121478 0
Chan.Cheah@health.wa.gov.au
Contact person for public queries
Name 121479 0
Ms Delaine Smith
Address 121479 0
ALLG
Ground Floor, 35 Elizabeth Street
Richmond, VIC 3121
Country 121479 0
Australia
Phone 121479 0
+61 03 8373 9701
Fax 121479 0
Email 121479 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 121480 0
Ms Delaine Smith
Address 121480 0
ALLG
Ground Floor, 35 Elizabeth Street
Richmond, VIC 3121
Country 121480 0
Australia
Phone 121480 0
+61 03 8373 9701
Fax 121480 0
Email 121480 0
delaine.smith@allg.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual patient data will not be shared publicly. Aggregate patient data and final results will be presented in the final report.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.