Cirmtuzumab Consolidation for Chronic Lymphocytic Leukemia

(Venetoclax Trial)

Overseen By Betty Cabrera, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must be taking: Venetoclax

Must not be taking: Steroids, Biologics, Chemotherapy, others

Disqualifiers: Infections, Hepatitis, Cirrhosis, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding cirmtuzumab to venetoclax (a medication for chronic lymphocytic leukemia, or CLL) effectively treats this type of blood cancer. Participants will receive the combination treatment for at least six cycles to determine its impact on reducing cancer cells. The trial seeks individuals who have been on venetoclax for at least a year and still have detectable CLL. This offers a chance to assess whether this new combination can significantly impact the disease. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you must not take certain cancer treatments like steroids, biologic agents, or chemotherapy shortly before starting the trial. You can continue taking venetoclax if you are already on it.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination of cirmtuzumab and venetoclax is generally well-tolerated by patients with chronic lymphocytic leukemia (CLL). Previous studies have demonstrated that venetoclax, which targets a protein that helps cancer cells survive, can work effectively with other cancer treatments. This combination aims to improve treatment results.

Regarding safety, venetoclax has been widely studied and proven effective in treating CLL. While it can cause some side effects, such as low white blood cell counts, these are usually manageable with medical help. Adding cirmtuzumab to venetoclax has not shown any unexpected safety issues in earlier studies. Testing has confirmed that this combination does not significantly increase risk.

Overall, while all treatments can have side effects, research indicates that the combination of cirmtuzumab and venetoclax has a promising safety profile. Participants should talk to their healthcare providers about any concerns to understand how this treatment might affect them personally. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of cirmtuzumab and venetoclax for treating chronic lymphocytic leukemia (CLL) because it targets cancer cells in a novel way. Unlike traditional treatments that often focus solely on killing cancer cells, cirmtuzumab is an antibody that specifically inhibits a protein called ROR1, which plays a crucial role in cancer cell survival and proliferation. When used with venetoclax, a drug that promotes cancer cell death by blocking the BCL-2 protein, this combination has the potential to more effectively reduce minimal residual disease, a key challenge in CLL treatment. This targeted approach could lead to deeper remissions and improved outcomes for patients.

What evidence suggests that cirmtuzumab consolidation might be an effective treatment for chronic lymphocytic leukemia?

In this trial, all participants will receive a combination of venetoclax and cirmtuzumab. Studies have shown that venetoclax effectively treats chronic lymphocytic leukemia (CLL), with many patients experiencing complete remission, meaning no signs of cancer were found. Research suggests that patients achieving undetectable minimal residual disease (uMRD) with venetoclax tend to have longer-lasting positive results. Cirmtuzumab, when combined with venetoclax, might enhance these outcomes by more precisely targeting cancer cells. While specific data on the cirmtuzumab-venetoclax combination is still being gathered, the success of venetoclax alone provides strong hope for this treatment approach. ^{2 6 7 8 9}

Who Is on the Research Team?

Benjamin M Heyman, MD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

This trial is for patients with chronic lymphocytic leukemia (CLL) who still have detectable disease after at least 12 months on venetoclax. They must not have significant uncontrolled conditions or infections, and women cannot be pregnant or breastfeeding. Those recently treated with certain therapies or having another malignancy may be excluded.

Inclusion Criteria

I stopped taking venetoclax over 6 months ago and my cancer is considered low risk.

My blood test shows more than 0.01% leukemia cells.

I am currently taking venetoclax.

Exclusion Criteria

Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: uncontrolled and/or active systemic infection (viral, bacterial or fungal), chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate, Child class B or C cirrhosis, treatment with any of the following within 7 days prior to the first dose of cirmtuzumab: steroid therapy for anti-neoplastic intent, biologic agent (monoclonal antibody) within 30 days for anti-neoplastic intent, chemotherapy (purine analog or alkylating agent) or target small molecule agent within 14 days or 5 half-lives (whichever is shorter), or has not recovered to less than CTCAE grade 2 clinically significant adverse effect(s)/toxicity(s) of previous therapy, CLL therapy, aside from venetoclax, history of other malignancy that could affect compliance with the protocol or interpretation of results (example: patients with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are generally eligible), women who are pregnant or lactating

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cirmtuzumab and venetoclax for a minimum of 6 cycles (28 days per cycle) as consolidation therapy

6-12 months

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

6-12 months

What Are the Treatments Tested in This Trial?

Interventions

• Cirmtuzumab
• Venetoclax

Trial Overview The study is testing the effectiveness of cirmtuzumab given to patients who are already taking venetoclax but still show signs of CLL. It's a phase 2 trial where all participants will receive cirmtuzumab to see if it can further reduce leukemia cells.

How Is the Trial Designed?

Group I: Cirmtuzumab + Venetoclax Experimental Treatment 2 Interventions

All patients will receive a minimum of 6 cycles (cycle = 28 days) of therapy with venetoclax and cirmtuzumab during the treatment period. For patients who achieve undetectable minimal residual disease (uMRD) positive after cycle 6, an additional 6 cycles of venetoclax and cirmtuzumab may be administered.

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

Approved in United States as Venclexta for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Approved in European Union as Venclyxto for:

• Chronic lymphocytic leukemia (CLL)
• Small lymphocytic lymphoma (SLL)
• Acute myeloid leukemia (AML)

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Oncternal Therapeutics, Inc

Industry Sponsor

Trials

7

Recruited

240+

Published Research Related to This Trial

The combination of venetoclax with rituximab showed remarkable efficacy and a manageable safety profile in treating chronic lymphocytic leukemia (CLL), both in relapsed/refractory cases and as a first-line therapy for high-risk patients.

Similarly, the combination of ibrutinib with venetoclax also demonstrated striking efficacy, suggesting that these combinations could become new standard treatment options for CLL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic lymphocytic leukemia at ASH 2017. Wanner, D., Steurer, M.[2020]

Venetoclax is an effective oral treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), showing durable responses and a manageable safety profile in clinical trials, including patients with poor prognostic factors.

In combination with rituximab, venetoclax significantly improved progression-free survival and achieved undetectable minimal residual disease compared to bendamustine plus rituximab, with benefits lasting for at least 36 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. Scott, LJ.[2020]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

The combination of venetoclax and obinutuzumab was found to be safe and well-tolerated in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia, with no dose-limiting toxicities observed during the study.

The treatment resulted in a high overall response rate of 95% in relapsed/refractory patients and 100% in previously untreated patients, with significant rates of undetectable minimal residual disease, indicating effective disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia. Flinn, IW., Gribben, JG., Dyer, MJS., et al.[2021]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic ... Venetoclax–obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data ...

3. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 Indication. VENCLEXTA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6624969/

Efficacy of venetoclax in relapsed chronic lymphocytic ... Patients with relapsed CLL achieving complete remission or undetectable MRD on venetoclax treatment have the most durable responses. Less durable responses are ...

5. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/progression-free-survival.html

durable progression-free survival without long-term treatment 1 VENCLEXTA efficacy results: durable progression-free survival without long-term treatment · VEN+G demonstrated durable PFS without long-term treatment · IRC- ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118474733

Safety and Efficacy of a Combination of Venetoclax (GDC ... Based on a safety review of data from this trial, the 600 mg cohort will not be explored. Response is first assessed before Cycle 4 according to 2008 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04501939?term=venetoclax&viewType=Table&rank=1

Cirmtuzumab Consolidation for Treatment of Patients With ... Must have detectable CLL/SLL (> 0.01% leukemia cells present); Must have received at least 12 months of venetoclax. Patients may be receiving venetoclax at the ...

8. researchgate.net researchgate.net/publication/336422869_Safety_and_Efficacy_of_a_Combination_of_Venetoclax_GDC-0199ABT-199_and_Obinutuzumab_in_Patients_with_RelapsedRefractory_or_Previously_Untreated_Chronic_Lymphocytic_Leukemia_-_Results_from_a_Phase_1b_S

Safety and Efficacy of a Combination of Venetoclax (GDC- ... Research studies also exposed that ABT-199 had a substantial sensitizing role in combination therapy with other anticancer drugs, like ...

9. venclextahcp.com venclextahcp.com/cll/side-effects/ven-g-safety-profile.html

VEN+G Safety Data for CLL/SLL - venclexta No ongoing treatment exposure1. The fixed duration of VEN+G results in limited treatment exposure. VEN+G safety from the CLL14 trial.