September 20, 2021
|
October 4, 2021
|
April 17, 2024
|
November 16, 2021
|
December 1, 2026 (Final data collection date for primary outcome measure)
|
Overall hematologic response rate [ Time Frame: baseline to 6 years ] defined as ≥25% reduction in serum IgM) during treatment compared to baseline in patients with IgM mediated symptomatic neuropathy treated with the combination acalabrutinib + rituximab (or biosimilar
|
Same as current
|
|
- Progression Free Survival [ Time Frame: Duration of time from start of treatment to time of objective disease progression (including initiation of new therapy or death) up to 6 years ]
Time from initiation of Acalabrutinib + rituximab therapy until disease progression (>25% increase in serum IgM and 500 mg/dL absolute increase).
- Time to next treatment [ Time Frame: Duration of time from start of treatment to next therapy or last follow-up up to 72 months ]
Time from initiation of Acalabrutinib + rituximab therapy until initiation of new line of therapy
- Overall Survival [ Time Frame: Duration of time from start of treatment to time of death or last follow-up up to 72 months ]
Time from initiation of therapy until death
- Complete Response Rate [ Time Frame: Duration of time from start of treatment to last follow-up up to 72 months. ]
Proportion of patients with a complete response. Complete response (CR) is defined as having resolution of WM related symptoms, normalization of serum IgM levels with complete disappearance of IgM paraprotein by immunofixation, and resolution of any adenopathy or splenomegaly. A complete response requires reconfirmation demonstrating normal serum IgM levels, and absence of IgM paraprotein by immunofixation by a measurement repeated at least 2 weeks later.
- Bone marrow response [ Time Frame: Cycle 12, yearly up to 4 years ]
Absolute change in bone marrow burden of disease from baseline in patients who have involvement at baseline.
- Number of Participants to Treatment Related Adverse Events [ Time Frame: Throughout the study and for 30 days after the last dose, up 4 years ]
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
- Very Good Partial Response (VGPR): [ Time Frame: Duration of time from start of treatment to last follow-up up to 72 months. ]
Proportion of patients with a very good partial response (VGPR) defined as >90% reduction in serum IgM levels, or normalization of serum IgM levels with persistent IgM monoclonal spike in SPEP or immunofixation.
- Partial Response (PR): [ Time Frame: Duration of time from start of treatment to last follow-up up to 72 months. ]
Proportion of patients with a Partial response (PR) is defined as achieving a >50% reduction in serum IgM levels.
- Minor Response (MR): [ Time Frame: Duration of time from start of treatment to last follow-up up to 72 months. ]
Proportion of patients with a minor response (MR) is defined 25-49% reduction in serum IgM levels.
- Rate of neuropathy response by INCAT-ISS [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on INCAT-ISS
- Rate of neuropathy response by INCAT disability score [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on INCAT disability score
- Rate of neuropathy response by MRC distal sum score [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on MRC distal sum score
- Rate of neuropathy response by 10-meter walk time [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on 10-meter walk time changes.
- Rate of neuropathy response by 9-hole peg test [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on 9-hole peg test.
- Rate of neuropathy response by VAS [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on Visual Analogue Scale.
- Rate of neuropathy response by I-RODS functional score [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on I-RODS functional score
- Rate of neuropathy response by Rausch built FSS [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on Rausch built Fatigue Severity Score
- Rate of neuropathy response by IN-QOL tool [ Time Frame: Cycles 3, 6, 9, 12 (each cycle is 28 days), and then yearly for the duration of the study up to 6 Years ]
The proportion of patients with improvement or stability in neuropathy based on IN-QOL tool
|
Same as current
|
Not Provided
|
Not Provided
|
|
ACALA-R In Predominantly Demyelinating IgM Mediated Neuropathy
|
Phase II Study on Acalabrutinib and Anti-CD20 Antibody in Patients With Predominantly Demyelinating Neuropathy With or Without Anti-MAG
|
In this research study, is combining a new treatment acalabrutinib with a standard treatment, rituximab or other CD20 antibody, to determine whether this combination is safe and effective for participants with Immunoglobulin (Ig) M monoclonal gammopathy of undetermined significance ( IgM MGUS) or Waldenström macroglobulinemia WM related neuropathies.
The names of the study drugs involved in this study are/is:
- Acalabrutinib
- Rituximab or similar CD20 antibody
|
This research study involves an experimental drug combination of a targeted therapy and a CD20 antibody.
The names of the study drugs involved in this study are/is:
- Acalabrutinib
- Rituximab or similar CD20 antibody
The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
The study treatment for up to 4 years and will be followed for 2 years after completion of study treatment.
It is expected that about 33 people will take part in this research study.
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.
The U.S. Food and Drug Administration (FDA) has not approved acalabrutinib for this specific disease but it has been approved for other uses.
The U.S. Food and Drug Administration (FDA) has not approved rituximab or similar CD20 antibody for this specific disease but it has been approved for other uses.
- Acalabrutinib is a targeted therapy that blocks a type of protein called Bruton Tyrosine Kinase (BTK) that helps cells live and grow. By blocking BTK, acalabrutinib may kill abnormal cells or stop them from growing. It has been FDA approved for mantle cell lymphoma (MCL).
- Rituximab, or biosimilar, is a type of therapy called an antibody that attacks CD20, a protein found on B-cells. Rituximab is approved by the FDA for treating non-Hodgkin lymphoma (NHL). Rituximab is often used to treat WM and IgM MGUS neuropathies. Biosimilars are FDA approved drugs that have been determined to be interchangeable with the original drug.
|
Interventional
|
Phase 2
|
Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment
|
- IgM MGUS
- Waldenstrom Macroglobulinemia
- Neuropathy;Peripheral
|
- Drug: Acalabrutinib
Dose per protocol, oral twice daily per cycle
Other Name: Calquence
- Drug: Rituximab
Premedications (including acetaminophen, an antihistamine, and a steroid) will be given per institutional guideline Dosage determined per protocol and cycle timepoint, Route IV or SQ per protocol and cycle timepoint, schedule per protocol and cycle timepoint
Other Name: Rituxan
|
Experimental: ACALABRUTINIB + RITUXIMAB/BIOSIMILAR
Acalabrutinib and rituximab (or biosimilar) with be contained in the treatment regimen.
Acalabrutinib will be administered twice daily, with 28 consecutive days defined as a treatment cycle. Acalabrutinib will be administered for 48 cycles or until disease progression or unacceptable toxicity.
Rituximab will be administered on Days 1, 8, 15, and 22 of Cycles 1 and 4. Participants will have study visits every cycle for cycles 1-6, then every 3 cycles, with the next visit at Cycle 9, then C12, C15, etc.
Participants will continue acalabrutinib until disease progression or intolerable adverse effect develops. They will be followed for up to 2 years after completion of 48 cycles of treatment or until death
Interventions:
- Drug: Acalabrutinib
- Drug: Rituximab
|
Not Provided
|
|
Recruiting
|
33
|
Same as current
|
October 1, 2028
|
December 1, 2026 (Final data collection date for primary outcome measure)
|
Inclusion Criteria:
- Participants must meet the following criteria on screening examination to be eligible to participate. Screening evaluations including consent, physical exam, and laboratory assessments will be done within 30 days prior to Cycle 1 Day 1. Bone marrow biopsy &aspirate, skin (fat) biopsy, EMG, and CT C/A/P will be done within 90 days prior to Cycle1 Day 1.
- Presence of an IgM monoclonal paraprotein on serum immunofixation electrophoresis
-
Diagnosis of IgM MGUS or Waldenstrӧm macroglobulinemia using the criteria from Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al.Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003. 30(2): 110-5.
-
WM diagnostic criteria
- IgM monoclonal gammopathy of any concentration
- Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation
- Intertrabecular pattern of bone marrow infiltration
- Surface IgM+, CD5 +/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138- immunophenotype* --- Variations from this immunophenotypic profile can occur. However, care should be taken to satisfactorily exclude other lymphoproliferative disorders. This is most relevant in CD5+ cases, for which chronic lymphocytic leukemia and mantle cell lymphoma require specific exclusion before a diagnosis of WM can be made.
-
IgM MGUS diagnostic criteria
- IgM monoclonal gammopathy of any concentration
- No bone marrow infiltration
- Presence of predominantly sensory neuropathy with predominant demyelinating features on nerve conduction studies.
- Modified Rankin Scale score of ≥1 with progressing symptoms or a score ≥2
- ECOG ≤2
- Age > 18 years
- Participants may not be on any active therapy for other malignancies with the exception of topical therapies for basal cell or squamous cell cancers of the skin
-
At the time of screening, participants must have acceptable organ and marrow function as defined below:
- Absolute neutrophil count≥1,000/uL (no growth factor permitted within previous 7 days)
- Platelets ≥100,000/uL (no platelet transfusions permitted within previous 7 days); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator.
- For participants with platelets <100,000 uL deemed to be attributable to other causes than IgM MGUS or WM, platelets must be ≥50,000 uL (no platelet transfusions permitted)
-
Hemoglobin ≥ 10 g/dL (transfusions permitted); patients may enroll below this threshold if not attributable to IgM MGUS or WM after consultation with Sponsor-Investigator.
-- For participants with hemoglobin <10 g/dL deemed to be attributable to other causes than IgM MGUS or WM, hemoglobin must be ≥7 g/dL(transfusions permitted)
- Total bilirubin < 1.5 x institutional ULN
- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN
- Estimated GFR ≥30 mL/min
- International normalized ratio (INR) ≤ 2 x ULN and activated partial thromboplastin time (aPTT) ≤ 2 x ULN. Patients with INR and/or aPTT >2 x ULN who have lupus anticoagulant may be enrolled.
- Females of childbearing potential (FCBP) must use highly effective contraception (see Appendix D) or have complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) while participating in the study; and 2) for at least 1 week after last dose of acalabrutinib and 12 months from last dose of rituximab/biosimilar. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test at screening.
- Men must agree to use a latex condom during treatment and for up to 1 week after the last dose of acalabrutinib and 12 months after the last dose of rituximab during sexual contact with a FCBP
- Ability to adhere to the study visit schedule and other protocol requirements
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
|
Sexes Eligible for Study: |
All |
|
18 Years and older (Adult, Older Adult)
|
No
|
|
United States
|
|
|
NCT05065554
|
21-439
|
Yes
|
Studies a U.S. FDA-regulated Drug Product: |
Yes |
Studies a U.S. FDA-regulated Device Product: |
No |
|
Plan to Share IPD: |
Yes |
Plan Description: |
The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research. |
Supporting Materials: |
Study Protocol |
Supporting Materials: |
Statistical Analysis Plan (SAP) |
Time Frame: |
Data can be shared no earlier than 1 year following the date of publication |
Access Criteria: |
Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu |
|
Shayna Sarosiek, MD, Dana-Farber Cancer Institute
|
Jorge J. Castillo, MD, Dana-Farber Cancer Institute, Sponsor Investigator
|
Shayna Sarosiek, MD
|
Jorge J. Castillo, MD
|
AstraZeneca
|
Principal Investigator: |
Shayna R. Sarosiek, MD |
Dana-Farber Cancer Institute |
|
Dana-Farber Cancer Institute
|
April 2024
|