Neoplasms

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Lymphoma

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Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

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Immunoproliferative Disorders

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Leukemia, B-Cell

Chronic Disease

Disease Attributes

Lymphosarcoma

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

B-cell Lymphoma

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Venetoclax

Obinutuzumab

Acalabrutinib

Antineoplastic Agents, Immunological

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Participants will receive acalabrutinib and venetoclax orally.

Participants will receive Venetoclax orally and Obinutuzumab via IV infusion.

A study of acalabrutinib plus venetoclax (AV) versus venetoclax plus obinutuzumab (VO) in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma.

This is a phase III prospective, multicenter, randomized, open-label trial.

After completion of the screening period, eligible participants will be randomized in a 1:1 ratio to each of the following intervention arms:

Arm A: Minimal Residual Disease (MRD)-limited finite AV therapy Arm B: MRD-limited finite VO therapy

The study consists of screening, treatment, and post-intervention follow-up periods. Participants will undergo safety and efficacy assessments during each period for each study arm. The duration of individual participant involvement in the study will be approximately 5 years.

All participants who discontinue study intervention will be followed for safety assessments and survival status. Safety/survival follow-up is not required if the participant permanently discontinues study intervention due to withdrawal of consent, loss to follow-up, or death

A Study of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

A Phase III Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

To assess whether minimal residual disease (MRD)-driven finite AV treatment is NI to MRD-driven finite VO treatment with respect to PFS. PFS is defined as the time from the date of randomization until date of objective progressive disease per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria as assessed by the investigator or death from any cause in the absence of progression.

To assess the effect of AV treatment compared with VO treatment on uMRD at sequential time points. Rate of PB uMRD is defined as proportion of participants achieving remission based on a clonoSEQ\^® assay result of \< 1 CLL cell per 100,000 leukocytes (\< 10 \^-5 ), after completion of 6 and 12 cycles of venetoclax (assessed at approximately 7/13 and 9/15 months for VO and AV, respectively), and at 24, 36, 48 and 60 months.

To assess the effect of AV treatment compared with VO treatment on uMRD at sequential timepoints. Rate of PB and BM uMRD is defined as \< 1 CLL cell per 10,000 leukocytes (\< 10\^-4) by flow cytometry, after completion of 12 cycles of venetoclax (assessed at approximately 13 and 15 months for VO and AV, respectively) and at 36 months.

To assess the effect of AV treatment compared with VO treatment on OS. OS is defined as the time from the date of randomization until death from any cause.

To assess the effect of AV treatment compared with VO treatment on EFS. EFS is defined as the time from the date of randomization to the first occurrence of disease progression, initiation of subsequent CLL therapy, or death from any cause.

To assess the effect of AV treatment compared with VO treatment on ORR. ORR is defined as the proportion of participants who achieve best response of Complete Response (CR), complete response with incomplete marrow recovery (Cri), nodular partial remission (nPR), or partial remission (PR) per iwCLL 2018 criteria as assessed by the investigator.

To assess the effect of AV treatment compared with VO treatment on ORR. CR rate (uMRD per iwCLL guidelines 2018) after completion of 12 cycles of venetoclax.

To assess symptoms, functional status and global health status/quality of life (QoL), in participants treated with AV versus VO using the EORTC QLQ-C30.

EORTC QLQ-C30 consists of 30 items and measures symptoms, functioning, and global health status/QoL for all cancer types. Questions are grouped into 5 multi-item functional scales, 3 multi-item symptom scales, a 2-item global QoL scale, 5 single items assessing additional symptoms commonly reported by cancer participants, and 1 item on the financial impact of the disease.

The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 Scoring Manual. An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales, each of the functional scales, and the global measure of health status scale. Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity.

To assess symptoms, functional status, and global health status/QoL, participants treated with AV versus VO using the EORTC QLQ-CLL17.

EORTC QLQ-CLL17 comprises 17 items grouped into 3 multi-item scales: 1) symptom burden, 2) physical condition/fatigue, and 3) worries/fears about health and functioning.

The EORTC QLQ-CLL17 will be scored according to the EORTC QLQ-C30 Scoring Manual. An outcome variable consisting of a score from 0 to 100 will be derived for each of the symptom scales, each of the functional scales, and the global measure of health status scale. Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales represent greater symptom severity.

To assess symptomatic toxicities patient perceived benefit-risk in participants treated with AV versus VO using the NCI PRO-CTCAE item for Bruising.

It was designed to be used as a companion to the Common Terminology Criteria for Adverse Events (CTCAE), the standard lexicon for adverse event reporting in cancer trials. The bruising item, which has a dichotomous yes/no response option, will be included in this study to capture patient-reported bruising.

To assess patient perceived benefit-risk of treatment in participants treated with AV versus VO using the PGI-BR.

PGI-BR consists of 4 study medication-related questions, one each on efficacy, side effects, convenience of use, and overall benefit-risk. Each item is scored separately, with the final item providing a single metric of a participant's overall benefit-risk assessment.

The response from each question will be semi-quantitative. Each question ranges from Very (negative, Somewhat \[negative\]), Neutral, Somewhat \[positive\], Very \[positive\].

To assess the safety and tolerability of AV treatment versus VO treatment in participants with previously untreated CLL/SLL.

AstraZeneca

Antirheumatic Agents

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Rituximab

Prednisolone

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Immunologic Factors

HDMP + rituximab as a means of debulking prior to initiating venetoclax.

* Patients will receive HDMP + Rituximab for 1 cycle, followed by reassessment of Tumor Burden,
* If Tumor Burden classification is low after HDMP + Rituximab (lymph nodes \< 5cm in diameter AND absolute lymphocyte count \< 25k/uL), patients will initiate venetoclax dose ramp-up, with ramp-up schedule according to venetoclax package insert.
* Patients who still have a disease burden (lymphadenopathy \> 5 cm or ALC \> 25k/iL) that meets criteria for medium or high risk of TLS after 1 cycle of HDMP + Rituximab are given the option to repeat a 2nd cycle of HDMP + Rituximab prior to venetoclax dose ramp-up.

Choi Michael, MD

The purpose of the study is to investigate whether the combination of rituximab and high dose methylprednisolone can be given together, can reduce the amount of cancer cells that are present prior to starting venetoclax, and therefore make it safer to take venetoclax. Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) will be treated in this study. Subjects will be assessed for their risk of tumor lysis syndrome (TLS), a potentially serious side effect associated with venetoclax and rituxan. TLS is caused by the fast breakdown of cancer cells. TLS can lead to kidney failure or abnormal heart rhythm. Depending on their TLS risk, patients will be assigned to one of two treatment arms. Patients who are at high risk for TLS at baseline will receive HDMP/Rituximab for 1 cycle before beginning venetoclax. Patients who are at low risk for TLS at baseline will not receive HDMP/Rituximab and will instead start directly with venetoclax. Once the proper dose of venetoclax is reached, both arms will continue venetoclax for up to 2 years and receive rituximab for 5 cycles. The purpose is to determine if HDMP/Rituximab prior to venetoclax is efficient at reducing tumor burden and lowering the risk of developing TLS. Although all of these drugs are approved by the FDA for the treatment of patients with CLL or SLL, and although the combination of rituximab and venetoclax is approved by the FDA for the treatment of patients with CLL or SLL, the combination and dosing schedule in this trial are considered experimental.

Objectives:

Primary:

1. To determine the percentage of patients who have a reduction of lymphadenopathy (from greater than to less than 5 cm in largest diameter) and/or absolute lymphocyte count (from greater than to less than 25k/uL) following 1 or 2 cycles of HDMP + rituximab.

Secondary:

1. To determine the rate of laboratory or clinical TLS with this strategy.
2. To determine the safety (CTCAE4) of this approach.
3. To determine the overall efficacy (iwCLL) of this overall strategy.
4. To determine the percentage of patients who have undetectable minimal residual disease in the bone marrow.

Endpoints:

Primary:

1. Percentage of patients that have a decrease in tumor burden from levels of disease that meet "Medium/High-tumor burden" criteria to meet "Low tumor burden" criteria for disease burden following 1 or 2 cycles of HDMP + Rituximab.

Secondary:

1. Percentage of patients that have a decrease in tumor burden from levels of disease that meet "Medium/High-tumor burden" c criteria to meet "Low tumor burden" criteria for disease burden following 1 cycle of HDMP + Rituximab.
2. Percentage of patients that have a decrease in tumor burden from levels of disease that meet "Medium/High-tumor burden" criteria to meet "Low tumor burden" criteria for disease burden following 2 cycles of HDMP + Rituximab.
3. Rate of laboratory TLS (from start of treatment until completion of venetoclax ramp-up)
4. Rate of clinical TLS (from start of treatment until completion of venetoclax ramp-up)
5. Adverse events by CTCAE4 definitions
6. Overall Response rate, Partial Response rate, and Complete response rate per iwCLL criteria after 9 months of venetoclax and at completion of treatment.
7. Undetectable minimal residual disease (MRD) rate based on bone marrow biopsy after 9 months of venetoclax, and at completion of treatment.

Single center, open-label, pilot/feasibility study to determine the feasibility of HDMP/R as a debulking approach prior to venetoclax.

Patients with CLL/SLL who require therapy, and have disease burden meeting criteria for Medium or High Risk Tumor Burden (based on: lymph nodes \>/= 5 cm in diameter and/or absolute lymphocyte count \>/= 25k/uL) are enrolled.

* Patients will receive HDMP + Rituximab for 1 cycle, followed by reassessment of Tumor Burden,
* If Tumor Burden classification is low after HDMP + Rituximab (lymph nodes \< 5cm in diameter AND absolute lymphocyte count \< 25k/uL), patients will initiate venetoclax dose ramp-up, with ramp-up schedule according to venetoclax package insert.
* Patients who still have a disease burden (lymphadenopathy \> 5 cm or ALC \> 25k/iL) that meets criteria for medium or high risk of TLS after 1 cycle of HDMP + Rituximab are given the option to repeat a 2nd cycle of HDMP + Rituximab prior to venetoclax dose ramp-up.

Upon completion of ramp-up (venetoclax to 400 mg), all patients will continue Venetoclax 400 mg (or highest tolerated dose) for up to 2 years. Patients will also continue rituximab 500 mg/m2 q 28 days through Cycle 6.

Endpoint Assessment:

1. Assessment of the disease burden after a maximum of 2 cycles of HDMP + Rituximab is the primary endpoint.
2. Assessment of the disease burden after 1 cycle of HDMP + Rituximab.
3. Assessment of the disease burden after 2 cycles of HDMP + Rituximab (for the subset of patients that do not meet criteria for low tumor burden after 1 cycle).
4. Clinical and laboratory TLS events between start of treatment and the completion of venetoclax dose-ramp up (Cycle 2, Day 1)
5. Presence or absence of detectable MRD in the marrow will be assessed after approximately 9 months of venetoclax and completion of treatment.
6. Radiology assessment after approximately 9 months of venetoclax and completion of study (unless prior imaging studies are without measurable disease)

Rituximab + High-Dose Methylprednisolone Debulking Prior to Venetoclax for CLL & SLL Patients

Rituximab and High-Dose Methylprednisolone Debulking Prior to Venetoclax for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma	NCT05057494	Chronic Lymphoc...	Acalabrutinib Venetoclax Obinutuzumab	18 Years - 130 Years	AstraZeneca
Rituximab + High-Dose Methylprednisolone Debulking Prior to Venetoclax for CLL & SLL Patients	NCT04981912	Chronic Lymphoc...	HDMP + rituxima...	-	University of California, San Diego

Spots Global Cancer Trial Database for chronic lymphocytic leukemia or small lymphocytic lymphoma