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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05864742




Registration number
NCT05864742
Ethics application status
Date submitted
1/05/2023
Date registered
18/05/2023
Date last updated
10/05/2024

Titles & IDs
Public title
Genetically Risk-Stratified Venetoclax, Ibrutinib, Rituximab (± Navitoclax) in Relapsed/Refractory Mantle Cell Lymphoma
Scientific title
A Phase II Study of Genetically Risk-Stratified Combination of Venetoclax, Ibrutinib and Rituximab (With and Without Navitoclax) in Patients With Relapsed and Refractory Mantle Cell Lymphoma (AIM2)
Secondary ID [1] 0 0
21/001
Universal Trial Number (UTN)
Trial acronym
Linked study record

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

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Ibrutinib
Treatment: Drugs - Venetoclax
Treatment: Drugs - Navitoclax
Treatment: Drugs - Rituximab

Experimental: Standard-Risk Cohort - Patients without the high-risk mutations (no 9p21.1-24.3 loss, no SMARCA2 or SMARCA4 mut/del) will be treated with ibrutinib, rituximab and venetoclax.

Experimental: High-Risk Cohort - Patients with the high-risk mutations (9p21.1-24.3 loss, SMARCA2 and/or SMARCA4 mut/del) will be treated with ibrutinib, rituximab, venetoclax and navitoclax.


Treatment: Drugs: Ibrutinib
560 mg daily continuously

Treatment: Drugs: Venetoclax
Oral daily. Dose escalation every 7 days (if no TLS) 20mg, 50mg, 100mg, 200mg and 400mg

Treatment: Drugs: Navitoclax
Oral daily. Dose-escalation every 14 days (if plt >75x10^9/L) 50mg, 100mg, 150mg, and 200mg (target dose)

Treatment: Drugs: Rituximab
375mg/m2, intravenous. To be given on day 1 of weeks 1, 2, 3, 4 of C1 and day 1 of C2-C8
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Depth of MCL response to venetoclax and ibrutinib in combination with rituximab as determined by MRD at 16 weeks.
Timepoint [1] 0 0
2.5 years

Eligibility
Key inclusion criteria
1. Patient must be = 18 years of age.

2. Patient must have a confirmed diagnosis of MCL according to World Health Organisation
([WHO] 2008) criteria, and have received at least one prior line of systemic therapy
for their disease. Patients recently commenced on ibrutinib (=4 weeks) will be allowed
to enrol as long as at the time of enrolment there is measurable disease and no
disease progression.

3. Patient requires treatment in the opinion of the investigator, and has at least one
site of assessable disease not previously irradiated (such as lymph node with largest
diameter =1.5cm, or unequivocal hepatomegaly/splenomegaly).

4. Patient has an Eastern Cooperative Oncology Group (ECOG) performance score of = 2 .

5. Patient must have adequate bone marrow function independent of growth factor support
at screening as follows:

- Absolute Neutrophil Count (ANC) = 0.75 x 109/L (neutropenia due to marrow
infiltration may be supported by growth factors)

- Platelets = 50 x 109/L (= 30 x 109/L if reduced counts due to marrow
infiltration; entry platelet count must be independent of transfusion within 7
days)

6. Patients must have adequate coagulation, renal, and hepatic function, per laboratory
reference range at screening as follows:

- Activated partial thromboplastin time (aPTT) and prothrombin time (PT) =1.5 × the
upper limit of normal (ULN)

- Calculated creatinine clearance of at least 30 mL/min using the Cockcroft-Gault
equation or a 24-hour urine collection (Appendix 2)

- Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) = 3.0 × ULN of
institution's normal range

- Bilirubin =1.5 × ULN. Patients with documented Gilbert's Syndrome may have a
bilirubin > 1.5 × ULN

7. Female patients of childbearing potential and non-sterile male patients (with
partner(s) of child bearing potential) must practice at least one of the following
methods of birth control with partner(s) from initial study drug administration to 90
days after the last dose of study drug:

- Total abstinence from sexual intercourse as the preferred life style of the
patient; periodic abstinence is not acceptable

- Surgically sterile partner(s); acceptable sterility surgeries are: vasectomy,
bilateral tubal ligation, bilateral oophorectomy or hysterectomy

- Intrauterine device

- Double-barrier method (contraceptive sponge, diaphragm or cervical cap with
spermicidal jellies or cream AND a condom)

- Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months
prior to study drug administration

8. Female patients of childbearing potential must have a negative serum (beta-human
chorionic gonadotropin [B-hCG]) or urine pregnancy test at screening. Women who are
pregnant or breastfeeding are ineligible for this study.

9. Male patients must agree to refrain from sperm donation, from initial study drug
administration until 90 days after the last dose of study drug.

10. Patient is able to swallow whole tablets.

11. Patient (or their legally acceptable representatives) must sign an informed consent
document indicating that they understand the purpose of and procedures required for
the study, including biomarkers, and are willing to participate in the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient has undergone an allogeneic stem cell transplant within the last 6 months or
currently has active graft-vs-host disease requiring the use of immunosuppressants.

2. Patient has active and uncontrolled autoimmune cytopenias (for 2 weeks), including
autoimmune haemolytic anaemia and immune thrombocytopenic purpura.

3. Patient has current central nervous system (CNS) involvement by MCL.

4. Patient currently receiving ibrutinib for >4 weeks or previously received a Bruton's
tyrosine kinase (BTK) inhibitor or B-cell lymphoma 2 (bcl-2) inhibitor.

5. Patient has received the following within 30 days prior to the first dose of study
drug:

• Monoclonal antibody given with anti-neoplastic intent

6. Patient has received any of the following within 14 days prior to the first dose of
study drug, or has not recovered to less than CTCAE grade 2 clinically significant
adverse effect(s)/toxicity(s) of the previous therapy:

- Any anti-cancer therapy including chemotherapy, or radiotherapy

- Investigational therapy, including targeted small molecule agents

7. Patient has received the following within 7 days prior to the first dose of study
drug:

• Steroid therapy given with anti-neoplastic intent

8. Patients requires ongoing therapy with:

- Potent CYP3A inhibitors (such as indinavir, ketoconazole, and clarithromycin)

- Potent CYP3A inducers (e.g., rifampin, phenytoin, carbamazepine or St. John's
Wort)

- Warfarin, or equivalent vitamin K antagonist

- Antiretroviral medications.

9. Patient has consumed the following within 3 days prior to the first dose of study
drug:

- Grapefruit, or

- Grapefruit products, or

- Seville oranges (including marmalade containing Seville oranges), or

- Star fruit

10. Patient has clinically significant cardiovascular disease such as uncontrolled
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by
the New York Heart Association Functional Classification

11. Patient has a life-threatening illness, medical condition, or organ system dysfunction
which, in the investigator's opinion, could compromise the patient's safety, interfere
with the absorption or metabolism of oral drugs, or put the study outcomes at undue
risk:

• Specifically, a patient with history of stroke or intracranial haemorrhage within 6
months prior to enrolment is excluded

12. Patient has a history of other active malignancies other than MCL within the past 2
years prior to study entry, with the exception of:

- Adequately treated in situ carcinoma of the cervix uteri

- Adequately treated basal cell carcinoma of the skin or localised squamous cell
carcinoma of the skin

- Previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent

13. Patient has active Hepatitis C Virus (HCV) or active Hepatitis B Virus (HBV) infection
or known history of human immunodeficiency virus (HIV) or any uncontrolled active
systemic infection requiring intravenous (IV) antibiotics.

14. Received live, attenuated vaccines within 4 weeks prior to the first dose of study
drug.

15. Major surgery within 4 weeks prior to the first dose of study drug.

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

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
7/09/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2029
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC
Recruitment hospital [1] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 0 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 0 0
Peter MacCallum Cancer Centre - Parkville
Recruitment postcode(s) [1] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 0 0
5042 - Bedford Park
Recruitment postcode(s) [3] 0 0
3000 - Parkville

Funding & Sponsors
Primary sponsor type
Other
Name
Peter MacCallum Cancer Centre, Australia
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This is an open label, multi-centre, phase II study in which RR MCL patients will be
genetically risk-stratified into Standard risk (no 9p21.1-24.3 loss, no SMARCA2 or SMARCA4
mut/del) and High risk (9p21.1-24.3 loss, SMARCA2 and/or SMARCA4 mut/del).

Patients without the high-risk mutations will be treated with ibrutinib, rituximab and
venetoclax. Patients with the high-risk mutations will be treated with ibrutinib, rituximab,
venetoclax and navitoclax.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05864742
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Mary-Ann Anderson
Address 0 0
Country 0 0
Phone 0 0
+61 3 8559 5000
Fax 0 0
Email 0 0
MaryAnn.Anderson@petermac.org
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05864742