Acalabrutinib + Chemotherapy for Non-Hodgkin's Lymphoma

Recruiting in Palo Alto (17 mi)

Overseen by Mark J Roschewski, M.D.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: CNS lymphoma, Pregnancy, Active infections, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

Background: Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma. Most people with this cancer can be cured. But those who are not cured have a poor prognosis. Researchers want to add another drug to standard treatment see if it can improve the cure rate. Objective: To see if the drug acalabrutinib given with rituximab and standard combination chemotherapy can improve the cure rate of aggressive B-cell lymphomas such as diffuse large B-cell lymphoma. Eligibility: People ages 18 and older with an aggressive B-cell lymphomas that have not been treated Design: Participants will be screened with: Blood and urine tests Physical exam Medical history Tumor biopsy Bone marrow biopsy: A needle will remove marrow from the participant s hipbone. Lumbar puncture: If necessary, a needle will remove fluid from the participant s spinal canal. Imaging scans Participants will take the study drug for up to 14 days. It is a pill taken 2 times a day. Then they will have more scans. They will get rituximab and chemotherapy. They may get these drugs through a needle in an arm vein. Or they may them through a tube placed in a vein in their chest or in their neck. They might also keep taking the study drug. Each treatment cycle lasts 21 days. They will have up to 6 cycles. Participants may have 4 doses of another drug injected into their spinal fluid. Participants will have repeats of the screening tests throughout the study. Participants will have a follow-up visit 30 days after their last treatment, then every 3 months for 2 years, then every 6 months for 3 years, and then yearly.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take medications that are moderate or strong CYP3A inhibitors or inducers, as these could interfere with the study drug.

What data supports the effectiveness of the drug Acalabrutinib in combination with chemotherapy for Non-Hodgkin's Lymphoma?

Acalabrutinib, a drug that blocks a protein important for cancer cell growth, has shown effectiveness in treating chronic lymphocytic leukemia (CLL) by significantly prolonging the time patients live without the disease getting worse. Additionally, combining Acalabrutinib with R-CHOP, a standard treatment for a type of Non-Hodgkin's Lymphoma, is being studied for its potential to improve treatment outcomes. ^{1 2 3 4 5}

Is the combination of Acalabrutinib and chemotherapy safe for treating Non-Hodgkin's Lymphoma?

Acalabrutinib, when combined with chemotherapy regimens like R-CHOP, is being studied for safety in treating Non-Hodgkin's Lymphoma. Previous studies on Acalabrutinib for other conditions, such as chronic lymphocytic leukemia, have shown it to have an acceptable safety profile, with common side effects including headache, diarrhea, and infections. Serious side effects like high blood pressure and heart rhythm issues were less common. ^{2 3 4 6 7}

How does the drug Acalabrutinib differ from other treatments for Non-Hodgkin's Lymphoma?

Acalabrutinib is a next-generation Bruton tyrosine kinase inhibitor that may offer improved potency and specificity, potentially leading to better efficacy and tolerability when combined with standard R-CHOP therapy for Non-Hodgkin's Lymphoma. This combination targets dysregulated B-cell receptor signaling, which is a feature of this type of lymphoma. ^{2 3 4 5 6}

Eligibility Criteria

Adults aged 18+ with untreated aggressive B-cell lymphomas, specifically diffuse large B-cell lymphoma or high-grade B-cell lymphoma. Participants must have measurable disease, adequate organ and marrow function, and be willing to use effective contraception. Pregnant women, those with CNS involvement by the cancer or certain other health conditions are excluded.

Inclusion Criteria

Effects of acalabrutinib on the developing human fetus are unknown. For these reasons the following measures apply: Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Women of childbearing potential (WOCBP) who are sexually active must agree to highly-effective contraception prior to study entry, for the duration of study participation, and for at least 2 days after the last dose of acalabrutinib or 12 months after the last dose of combined chemotherapy, whichever is later. Male subjects must use highly effective contraception prior to study entry, for the duration of study participation, and for 12 months after the last dose of combined chemotherapy; there is no contraception timing requirement post-last dose of acalabrutinib alone if male subject does not initiate chemotherapy on study after the acalabrutinib window. Participants must not be planning to conceive or father children within the projected duration of the trial, starting with the pre-screening/screening visit through 2 days after the last dose of acalabrutinib or 12 months after the last dose of combined chemotherapy, whichever is later. Ability of patient to understand and the willingness to sign a written informed consent document. Any HIV status will be included in this study; status must be confirmed prior to enrollment.

I have an aggressive type of B-cell lymphoma and have not been treated for it.

I can provide a tumor sample for study, or I'm willing to have a biopsy if needed.

Exclusion Criteria

I do not have an active hepatitis B infection or a positive hepatitis B PCR test.

I do not have any other cancer requiring ongoing treatment.

My lymphoma has spread to my brain or spinal cord.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for tests and biopsies

Initial Treatment

Participants receive acalabrutinib for 14 days to assess initial response

2 weeks

1 visit for drug administration and assessment

Chemoimmunotherapy

Participants receive R-CHOP or DA-EPOCH-R, with or without acalabrutinib, based on initial response

18 weeks

6 cycles of 21 days each

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, then every 6 months for 3 years, then yearly

Treatment Details

Interventions

• Acalabrutinib (Bruton's Tyrosine Kinase (BTK) Inhibitor)
• CHOP (Chemotherapy)
• DA-EPOCH (Chemotherapy)
• Rituximab (Monoclonal Antibodies)

Trial Overview The trial is testing if adding acalabrutinib (a pill) to standard chemotherapy regimens (DA-EPOCH-R or R-CHOP) along with rituximab improves cure rates in aggressive B-cell lymphomas like diffuse large B-cell lymphoma. The treatment includes up to six cycles of therapy lasting 21 days each.

Participant Groups

Group I: 1 Experimental Treatment 4 Interventions

Acalabrutinib 100 mg orally twice a day for 14 days; Following window: patients with \> or = to 25% tumor reduction, treat with DA-EPOCH-R or R-CHOP + acalabrutinib 100mg orally twice a day for the first 10 days, for 6 cycles; whereas, patients with \<25% tumor reduction, treat with DA-EPOCH-R or R-CHOP alone for 6 cycles

Acalabrutinib is already approved in United States, European Union for the following indications:

🇺🇸 Approved in United States as Calquence for:

• Mantle cell lymphoma
• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma

🇪🇺 Approved in European Union as Calquence for:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Mantle cell lymphoma

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

References

1. United States pubmed.ncbi.nlm.nih.gov

Randomized study comparing doxorubicin, cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (ACOMLA) with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-B) in the treatment of diffuse histiocytic lymphoma. [2015] Two combination chemotherapy programs, ACOMLA (doxorubicin, cyclophosphamide, vincristine, methotrexate and leucovorin rescue, and cytarabine) and CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), were evaluated in 29 prospective randomized patients with advanced diffuse histiocytic lymphoma. A complete response was achieved in 13 of the 15 patients (87%) treated with CHOP-B and in nine of the 14 patients (64%) treated with ACOMLA. The overall complete response rate was 75%. Two patients treated with ACOMLA and none of the CHOP-B-treated patients have relapsed. Median followup is 32 months for ACOMLA patients and 26 months for CHOP-B patients. Actuarial freedom from relapse at 2 years is 49.9% for ACOMLA and 93.3% for CHOP-B (P = 0.04). Toxicity was substantial, with eight nonfatal episodes of sepsis and three drug-related deaths. There have been no central nervous system relapses. Although patients treated with CHOP-B have a better response rate, the small numbers of patients treated to date preclude definitive conclusions.

2. England pubmed.ncbi.nlm.nih.gov

ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial. [2021] Background: Over 13,000 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton's tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability. Methods: ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints. Discussion:&#160;ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL. Trial registration: EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN 13626902 (registered 07 March 2017).

3. England pubmed.ncbi.nlm.nih.gov

EMA Review of Acalabrutinib for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia. [2021] On November 5, 2020, a marketing authorization valid through the European Union (EU) was issued for acalabrutinib monotherapy or acalabrutinib in combination with obinutuzumab (AcalaObi) in adult patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) and also for acalabrutinib monotherapy in adult patients with relapsed or refractory (RR) CLL. Acalabrutinib inhibits the Bruton tyrosine kinase, which plays a significant role in the proliferation and survival of the disease. Acalabrutinib was evaluated in two phase III multicenter randomized trials. The first trial (ACE-CL-007) randomly allocated acalabrutinib versus AcalaObi versus chlorambucil plus obinutuzumab (ChlObi) to elderly/unfit patients with TN CLL. The progression-free survival (PFS), as assessed by an independent review committee, was superior for both the AcalaObi (hazard ratio [HR], 0.1; 95% confidence interval [CI], 0.06-0.17) and acalabrutinib (HR, 0.2; 95% CI, 0.13-0.3) arms compared with the ChlObi arm. The second trial (ACE-CL-309) randomly allocated acalabrutinib versus rituximab plus idelalisib or bendamustine to adult patients with RR CLL. Also in this trial, the PFS was significantly longer in the acalabrutinib arm (HR, 0.31; 95% CI, 0.20-0.49). Adverse events for patients receiving acalabrutinib varied across trials, but the most frequent were generally headache, diarrhea, neutropenia, nausea, and infections. The scientific review concluded that the benefit-risk ratio of acalabrutinib was positive for both indications. This article summarizes the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Acalabrutinib was approved in the European Union for the treatment of adult patients with chronic lymphocytic leukemia who have not received treatment before and for those who have received therapy but whose disease did not respond or relapsed afterward. Acalabrutinib resulted in a clinically meaningful and significant lengthening of the time from treatment initiation to further disease relapse or patient's death compared with standard therapy. The overall safety profile was considered acceptable, and the benefit-risk ratio was determined to be positive.

4. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. [2022] Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator's choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1-month follow-up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow-up results. Patients with R/R CLL received oral acalabrutinib 100&#8201;mg twice daily until progression or unacceptable toxicity, or investigator's choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow-up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator-assessed progression-free survival (PFS) versus IdR/BR (median, not reached [NR] vs 16.8 months; P &lt; 0.001); 42-month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42-month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), grade &#8805;3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow-up, acalabrutinib maintained favorable efficacy versus standard-of-care regimens and a consistent tolerability profile in patients with R/R CLL.

5. United States pubmed.ncbi.nlm.nih.gov

Matching-adjusted indirect comparisons of safety and efficacy of acalabrutinib versus other targeted therapies in patients with treatment-naïve chronic lymphocytic leukemia. [2021] Acalabrutinib is a highly selective, potent, next-generation, covalent Bruton tyrosine kinase inhibitor with minimal off-target activity. Matching-adjusted indirect comparisons (MAICs) were performed to estimate the safety and efficacy of acalabrutinib compared to other targeted therapies for treatment-na&#239;ve patients with chronic lymphocytic leukemia (CLL). Individual patient data for acalabrutinib (ELEVATE-TN trial) were matched to aggregate baseline characteristics for comparators. After matching, acalabrutinib (with or without obinutuzumab) showed improved safety outcomes, except for increased risk of neutropenia (p&#8201;&lt;&#8201;0.001) for acalabrutinib plus obinutuzumab versus ibrutinib and increased risk of leukopenia (p&#8201;&lt;&#8201;0.05) for acalabrutinib (with or without obinutuzumab) versus venetoclax plus obinutuzumab. There was no statistically significant difference in progression-free survival between acalabrutinib (with or without obinutuzumab) and any of the comparators. This MAIC demonstrated a favorable safety profile for acalabrutinib-based therapy compared with other targeted therapies in treatment-na&#239;ve patients with CLL, without compromising efficacy.

6. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib: Managing Adverse Events and Improving Adherence in Patients With Mantle Cell Lymphoma. [2022] Acalabrutinib is a selective Bruton tyrosine kinase inhibitor approved for patients with relapsed or refractory mantle cell lymphoma, an aggressive B-cell malignancy. Treatment-related adverse events (AEs) can have a negative effect on treatment adherence.

7. United States pubmed.ncbi.nlm.nih.gov

Acalabrutinib in treatment-naive chronic lymphocytic leukemia. [2022] Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.