Trial Review

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
Help: Registration number
ACTRN12626000174381p
Ethics application status
Help: Ethics application status
Not yet submitted
Date submitted
Help: Date submitted
12/01/2026
Date registered
Help: Date registered
10/02/2026
Date last updated
Help: Date last updated
31/08/2026
Date data sharing statement initially provided
Help: Data sharing statement date
10/02/2026
Type of registration
Help: Type of registration
Prospectively registered

Titles & IDs
Public title
ALLG NHL43: An open-label multi-centre international phase 2 trial to evaluate the safety and efficacy of two years fixed duration therapy with sonrotoclax in combination with Tacabrutideg and rituximab in patients with treatment naïve or BTKi naïve/intolerant Waldenström Macroglobulinemia (WM).
Scientific title
An ALLG open-label multi-centre international phase 2 trial to evaluate the safety and efficacy of two years fixed duration therapy with sonrotoclax in combination with the Tacabrutideg and rituximab in patients with treatment naïve or BTKi naïve/intolerant Waldenström Macroglobulinemia (WM).
Additional trial identifiers [1] 316295 0
SOUNDER
Universal Trial Number (UTN)
Trial acronym
Related trial records

Health condition
Health condition(s) studied:
Waldenström Macroglobulinemia (WM) 340340 0
Condition category
Condition code
Cancer 336540 336540 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of the intervention or exposure
Patients will receive a fixed-duration triplet therapy consisting of Sonrotoclax, Tacabrutideg, and Rituximab for Waldenström Macroglobulinemia (WM). There will be 2 cohorts recruited to this study: 1) treatment-naive WM and 2) Relapsed or Refractor (R/R) WM patients who have received one prior line of therapy that did not include a Bruton Tyrosine Kinase (BTK) inhibitor. This is a single-arm, open-label Phase II study.

Treatment cycles are 28 days long. The total treatment duration is 2 years (25 cycles).

-Tacabrutideg will be administered orally at a dose of 200 mg once daily starting from Cycle 1 on Day 1 and continued until the end of treatment (EOT) at 2 years (Cycle 25 on Day 28).
-Sonrotoclax will commence at Cycle 2 on Day 1 with a 4-day ramp-up schedule:
Ramp-up doses: Day 1: 40 mg, Day 2: 80 mg, Day 3: 160 mg, Day 4: 320 mg.
Thereafter, Sonrotoclax will be administered orally at 320 mg once daily until EOT (2 years/Cycle 25 on Day 28).
-Rituximab will be administered intravenously at 375 mg/m² on Day 1 of Cycles 4, 5, 6, and 7, and then every 3 cycles (Cycles 10, 13, 16, and 19).

Safety lead-in reviews will occur after the first 10 patients complete the Sonrotoclax ramp-up and after 20 patients have received 9 months of therapy. The Trial Management Committee and Safety and Data Monitoring Committee will review patient response, tolerability, and adverse events at scheduled intervals to determine continuation or modification of therapy. Monitoring of adverse events and tolerability is continuous throughout the study. Follow up will be for three years.

All treatment will be administered by the study team (i.e., registered nurse, the lead physician, physicians listed on the trial to assist the lead physician). Drug accountability will be performed by the administering institutions to assess compliance through pharmacy dispensing logs, dose administration records, and verifying patient diaries.
Intervention code [1] 332943 0
Treatment: Drugs
Description of the comparator or control
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 344053 0
Very Good Partial Response (VGPR) Rate
Timepoint [1] 344053 0
2 year post treatment commencement
Secondary outcome [1] 456577 0
Time-to-next-treatment (TTNT)
Timepoint [1] 456577 0
End of trial and during follow-up (every 3 months for 3 years).
Secondary outcome [2] 456578 0
Progression-Free Survival (PFS)
Timepoint [2] 456578 0
From the date of registration to the date of progression or death if progressive disease (PD) is not recorded. During treatment and every 3 months of 3 year follow-up.
Secondary outcome [3] 456579 0
Overall Survival (OS)
Timepoint [3] 456579 0
From the date of registration to the date of death from any cause.
Secondary outcome [4] 456580 0
Overall Response Rate (ORR)
Timepoint [4] 456580 0
At end of treatment (2 years)
Secondary outcome [5] 456581 0
VGPR rate at 12 months
Timepoint [5] 456581 0
12 months post treatment commencement
Secondary outcome [6] 456583 0
Measureable Residual disease (MRD) negativity
Timepoint [6] 456583 0
Baseline, Cycle4, Cycle7, Cycle10, Cycle13, Cycle16, Cycle19, Cycle22, and end of treatment (EOT) in PB samples. Baseline, Cycle13, EOT in BM samples
Secondary outcome [7] 456585 0
Duration of Response (DOR)
Timepoint [7] 456585 0
End of treatment and every 3 months of 3 year follow-up.
Secondary outcome [8] 456591 0
VGPR rate in CXCR4 mutated patients
Timepoint [8] 456591 0
12 months and 2 years of treatment
Secondary outcome [9] 456592 0
Time to first response
Timepoint [9] 456592 0
Baseline, Cycle4, Cycle7, Cycle10, Cycle13, Cycle16, Cycle19, Cycle22, and end of treatment (EOT) in PB samples. Baseline, Cycle13, EOT in BM samples.
Secondary outcome [10] 456593 0
Change in haemoglobin levels
Timepoint [10] 456593 0
Every cycle during treatment; every 3 months of 3 year follow up.
Secondary outcome [11] 456594 0
Frequency of Grade 3 or higher adverse events (AEs) and severe adverse events (SAEs), such as febrile neutropenia and tumour lysis syndrome.
Timepoint [11] 456594 0
Continuous monitoring from start of treatment until end of 3 year follow up.
Secondary outcome [12] 456595 0
Quality of Life (QoL)
Timepoint [12] 456595 0
Baseline, every cycle until C13, EOT, and every 3 months during 3 year follow-up.
Secondary outcome [13] 456596 0
Health Economics
Timepoint [13] 456596 0
At end of trial and end of 3 year follow-up.
Secondary outcome [14] 456597 0
Rate of Secondary Primary Malignancies
Timepoint [14] 456597 0
Throughout treatment and follow-up.

Eligibility
Key inclusion criteria
1. Provision of signed and dated written informed consent.
2. Age greater than or equal to 18 years.
3. Histologically confirmed diagnosis of Waldenström Macroglobulinemia (WM) as per World Health Organization (WHO) criteria.
4.Measurable disease as defined by a serum immunoglobulin M (IgM) level greater than 5 grams per litre (g/L).
5. Meeting at least one criterion for treatment according to consensus panel criteria from the Seventh International Workshop on Waldenström Macroglobulinemia (Dimopoulos et al., 2014).
Clinical indications for initiation of therapy:
a. Recurrent fever, night sweats, weight loss, fatigue
b. Hyperviscosity
c. Lymphadenopathy that is either symptomatic or bulky (greater than or equal to 5 centimetres [cm] in maximum diameter)
d. Symptomatic hepatomegaly and/or splenomegaly
e. Symptomatic organomegaly and/or organ or tissue infiltration
f. Peripheral neuropathy due to WM
Laboratory indications for initiation of therapy:
g. Symptomatic cryoglobulinemia
h. Cold agglutinin anaemia
i. Immune haemolytic anaemia and/or thrombocytopenia or nephropathy related to WM
j. Amyloidosis related to WM
k. Haemoglobin less than or equal to 10 grams per decilitre (g/dL)
l. Platelet count less than 100 × 10^9 per litre (L)
6. Patients with relapsed or refractory (R/R) WM must also have received at least one prior line of therapy for WM (a line of therapy is considered greater than or equal to two consecutive cycles of systemic anticancer regimen, or at least four doses of rituximab monotherapy).
7. Females of childbearing potential must use an effective method of contraception or practice absolute abstinence for 28 days prior to therapy, during treatment, and at least 30 days after treatment discontinuation. Approved methods of birth control are:
a) Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) associated with the inhibition of ovulation, initiated at least 28 days prior to randomisation. Also, patients must use a barrier method during this trial from cycle 1 day 1 (C1D1) administration to 30 days after the last dose of treatment.
b) Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 28 days prior to registration. Patients must use a barrier method during this trial from C1D1 to 30 days after the last dose of trial treatment.
c) Bilateral tubal occlusion/ligation or bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a hysterosalpingogram confirms success of the procedure.
d) Vasectomised partner(s) provided the vasectomized partner verbally confirms receipt of medical assessment of the surgical success, vasectomy occurred more than 3 months prior to screening, and is the sole sexual partner of the WOCBP trial patient.
e) Intrauterine device (IUD).
f) Intrauterine hormone-releasing system (IUS).
g) True abstinence: Refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the subject [periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable].
8. Male patients must use contraception measures one week prior to commencement of trial drug, during treatment with trial drug, and at least three months after discontinuation of treatment.
9. Patients must agree not to donate blood, semen, or sperm while on trial treatment and for at least three months after treatment discontinuation.
10. Adequate haematological function at screening as defined by:
a. Absolute neutrophil count (ANC) greater than 1.0 × 10^9/L
i. Screening haematology results confirming ANC eligibility must be dated at least 14 days after the last pegfilgrastim dose and at least seven days after the last filgrastim or other myeloid growth factor dose.
b. Platelet count greater than 50 × 10^9/L
Prospective patients must be off growth factor support for greater than or equal to seven days and/or transfusions for greater than or equal to three days prior to the screening test date.
c. International Normalized Ratio (INR) less than or equal to 1.5 and activated partial thromboplastin time (aPTT) less than or equal to 1.5 × upper limit of normal (ULN) (patients on therapeutic anticoagulation may have aPTT greater than 1.5 × ULN as long as it is within the therapeutic range for the medication that they are receiving).
11. Adequate renal and hepatic function at screening as defined by:
a. Total bilirubin less than or equal to 1.5 × ULN (unless documented Gilbert Syndrome).
b. Alanine aminotransferase (ALT) less than or equal to 2.5 × ULN.
c. Aspartate aminotransferase (AST) less than or equal to 2.5 × ULN.
d. Calculated creatinine clearance greater or equal to 30 millilitres per minute (mL/min) – according to Cockcroft-Gault formula (see Appendix 3).
12. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2 at screening.
13. Life expectancy greater than or equal to six months.
14. Co-enrolment in the WhiMSICAL study (CH62/6/2025-042), Waldenström Macroglobulinemia Study Investigating Clinical Outcomes and Quality of Life.
15. Ability to provide written informed consent and to understand and comply with the requirements of the trial.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Healthy volunteers
No
Key exclusion criteria
1. Prior therapy with a Bruton Tyrosine Kinase (BTK) inhibitor, unless the BTK inhibitor was ceased within six months of commencing treatment due to intolerance. (Reasons for BTKi intolerance will be clearly documented a priori, and whether the patient should be consented and screened must be discussed with the SOUNDER CI and NHL43 CRA).
2. Prior therapy with Tacabrutideg or another BTK degrader, Sonrotoclax or another B-cell lymphoma 2 (BCL2) inhibitor.
3. Any immunoglobulin M (IgM) monoclonal gammopathy of clinical significance without unequivocal evidence of bone marrow (BM) involvement with clonal lymphoplasmacytic infiltrate. This includes, but is not limited to, patients with associated cold agglutinin disease, type I and II cryoglobulinemia, IgM-associated peripheral neuropathy, Schnitzler syndrome, and IgM-associated amyloid light-chain (AL) amyloidosis.
4. Active malignancy (other than Waldenström Macroglobulinemia [WM]) within the past two years, except for curatively treated skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localised Gleason score less than or equal to six prostate cancer.
5. Clinically significant cardiovascular disease including the following:
a. Myocardial infarction less than or equal to six months before the date screening commences.
b. Unstable angina less than or equal to three months before the date screening commences.
c. History of cardiovascular arrhythmias including sustained ventricular tachycardia, ventricular fibrillation, and Torsades de Pointes.
d. New York Heart Association (NYHA) class III or IV congestive heart failure.
e. Uncontrolled hypertension, defined as equal or greater than 160/100 mmHG on two measurements, or as deemed by the treating investigator.
f. History of or active Mobitz II second- or third-degree heart block without a permanent pacemaker in place.
g. Heart rate-corrected QT interval based on Fridericia’s formula (QTcF) greater than 480 milliseconds.
6. Underlying medical conditions that, in the investigator’s opinion, will render the administration of trial drug hazardous or obscure the interpretation of safety or efficacy results.
7. Women who are pregnant or lactating.
8. Patient has toxicities from previous anti-cancer therapies that have not resolved to baseline levels or to grade 1 or less, except for alopecia, peripheral neuropathy, and haematologic toxicity.
9. Transformation to aggressive lymphoma, such as diffuse large B-cell lymphoma. If transformation is suspected, a biopsy of the suspected area is required to exclude transformation.
10. Prior grade 4 (CTCAE V6) infusion related reaction to Rituximab.
11. History of stroke or intracranial haemorrhage within six months of first dose of the trial drugs.
12. Active infection (viral, bacterial, or fungal) requiring systemic anti-microbial treatment at the time of screening or within the previous two weeks prior to the first dose of trial treatment. Note that prophylactic anti-microbials (e.g., valaciclovir for herpes simplex virus [HSV]/varicella zoster virus [VZV] or entecavir for a history of hepatitis B) are allowed.
13. Positive serology for human immunodeficiency virus (HIV).
14. Active hepatitis B infection (defined as the presence of detectable hepatitis B virus [HBV] deoxyribonucleic acid [DNA] or hepatitis B surface antigen [HBsAg]). Patients who are hepatitis B core antibody (HBcAb) positive but are HBV DNA and HBsAg negative are eligible. These patients will have monthly monitoring of HBV DNA for the first year of the trial then at a frequency recommended by the local investigator / infectious disease service for the duration of the trial. These patients will receive appropriate anti-viral prophylaxis, with entecavir or similar, according to advice from the infectious disease service. Please note that patients who have received intravenous immunoglobulin (IVIG) may have false positive HBcAb results. In such patients, if HBV DNA and HBsAg are negative, prophylaxis may be omitted if deemed unnecessary by the infectious disease service, but monitoring of HBV DNA levels is still required.
15. Active hepatitis C, defined by the detection of hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR). Patients who have received treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable.
16. Received a live, attenuated vaccine within 28 days prior to initiation of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live, attenuated vaccines and are not allowed. Experimental and/or non-authorized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations are not allowed.
17. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the trial drugs.
18. Receiving treatment with any moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitor or moderate or strong CYP3A4 inducer less than or equal to 14 days or five half-lives (whichever is shorter) before the first dose of Sonrotoclax or requiring ongoing treatment with a moderate or strong CYP3A inhibitor or a moderate or strong CYP3A inducer.
19. Use of the following substances prior to the first dose of the study drug:
a. Systemic chemotherapy or radiation – less than or equal to 14 days (or five half-lives, whichever is shorter) before the first dose of the trial drug.
b. Corticosteroid given with antineoplastic intent (symptom control will not be considered as antineoplastic intent) – less than or equal to seven days before the first dose of the trial drug.
c. Any biologic and/or immunologic-based anticancer therapy – less than or equal to 28 days (or five half-lives, whichever is shorter).
20. Requires ongoing systemic (defined as greater than or equal to 10 milligrams per day [mg/day] of prednisone or equivalent) corticosteroid treatment. Patients on systemic corticosteroids at a dose of equal or greater than 20mg/day of prednisone or equivalent for greater or equal to 14 consecutive days within 4 weeks before the first dose of trial drug are excluded regardless of intent. Such higher dose systemic corticosteroids must be discontinued greater than or equal to seven days before the first day of trial treatment.
21. Patients with known contraindications to azole antifungal agents, including hypersensitivity reactions.
22. Prior invasive fungal infection.
23. History of a severe bleeding disorder such as haemophilia A, haemophilia B, or von Willebrand disease (patients with acquired von Willebrand syndrome due to WM are eligible), or history of spontaneous bleeding requiring blood transfusion or other medical intervention.
24. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist.
25. Patient has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient, or that could prevent, limit, or confound the protocol-specified assessments.

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 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/09/2026
Actual
Date of last participant enrolment
Anticipated
15/09/2029
Actual
Date of last data collection
Anticipated
15/09/2034
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 27743 0
United Kingdom
State/province [1] 27743 0
Country [2] 28483 0
New Zealand
State/province [2] 28483 0

Funding & Sponsors
Funding source category [1] 320892 0
Other Collaborative groups
Name [1] 320892 0
Australasian Leukaemia and Lymphoma Group
Country [1] 320892 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Country
Australia
Secondary sponsor category [1] 323589 0
None
Name [1] 323589 0
Address [1] 323589 0
Country [1] 323589 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 319434 0
Sydney Local Health District HREC – Concord Repatriation General Hospital
Ethics committee address [1] 319434 0
Ethics committee country [1] 319434 0
Australia
Date submitted for ethics approval [1] 319434 0
15/06/2026
Approval date [1] 319434 0
Ethics approval number [1] 319434 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 147314 0
Prof Judith Trotman
Address 147314 0
Concord Repatriation General Hospital Hospital Road, Concord NSW 2139
Country 147314 0
Australia
Phone 147314 0
+61 02 97675154
Fax 147314 0
Email 147314 0
[email protected]
Contact person for public queries
Name 147315 0
Delaine Smith
Address 147315 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 147315 0
Australia
Phone 147315 0
+61 03 83739701
Fax 147315 0
Email 147315 0
[email protected]
Contact person for scientific queries
Name 147316 0
Delaine Smith
Address 147316 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 147316 0
Australia
Phone 147316 0
+61 03 83739701
Fax 147316 0
Email 147316 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers
Conditions for requesting access:
• Yes, conditions apply:
• Requires review on a case-by-case basis by the trial custodian, sponsor or data sharing committee
What individual participant data might be shared?
• All de-identified individual participant data
What types of analyses could be done with individual participant data?
• Any type of analysis (i.e. no restrictions on data re-use)
When can requests for individual participant data be made (start and end dates)?
From:
3 months after publication

To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• Data sharing request system: Health Data Australia catalogue (e.g. https://researchdata.edu.au/health/)


Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]


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.