8-Chloroadenosine + Venetoclax for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: CNS leukemia, Cardiovascular disability, others

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

Compensation: Varies

Number of Visits: 33

Duration: 16 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial tests the safety, side effects, and best dose of a new 8-chloroadenosine in combination with venetoclax in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). 8-Chloroadenosine may help block the formation of growths that may become cancer. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving 8-chloroadenosine in combination with venetoclax may help prevent the disease from coming back in patients with acute myeloid leukemia.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot use certain investigational agents, chemotherapy, or specific substances like grapefruit and St. John's Wort close to starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination 8-Chloroadenosine and Venetoclax for treating Acute Myeloid Leukemia?

Research shows that Venetoclax, when combined with low-dose cytarabine, improves survival and response rates in patients with acute myeloid leukemia who cannot undergo intensive chemotherapy. This suggests that Venetoclax can be effective in treating this condition. ^{1 2 3 4 5}

What safety data exists for 8-Chloroadenosine and Venetoclax in humans?

8-Chloroadenosine has been tested in early clinical trials for blood cancers, and no obvious blood-related toxicity was observed in mice at certain doses. Venetoclax, also known as Venclexta, has been used in various conditions and is generally considered safe, but specific side effects can occur, so it's important to discuss with a healthcare provider. ^{6 7 8 9 10}

How is the drug combination of 8-Chloroadenosine and Venetoclax unique for treating acute myeloid leukemia?

This treatment is unique because it combines 8-Chloroadenosine with Venetoclax, a drug known for its effectiveness in improving response rates and survival in acute myeloid leukemia (AML) when used with other agents. Venetoclax works by targeting a protein that helps cancer cells survive, and its combination with 8-Chloroadenosine may offer a novel approach to enhance treatment outcomes for AML patients. ^{1 2 11 12 13}

Research Team

Vinod Pullarkat

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

Adults (18+) with relapsed or refractory Acute Myeloid Leukemia who have failed at least one line of therapy, are not eligible for stem cell transplant soon, and do not have active central nervous system leukemia or other serious conditions. Participants must be able to swallow capsules, not be pregnant or breastfeeding, and agree to use effective birth control.

Inclusion Criteria

I have relapsed and am not eligible for a specific stem cell transplant.

I am 18 years old or older.

My condition is newly diagnosed acute myeloid leukemia.

Exclusion Criteria

I have no active cancer except possibly skin, bladder, prostate, breast, or cervical cancer that hasn't spread.

I have been diagnosed with acute promyelocytic leukemia.

I cannot swallow pills or have a condition affecting my gut's ability to absorb nutrients.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 8-Cl-Ado intravenously over 4 hours daily on days 1-5 and venetoclax orally once daily on days 1-28. Treatment repeats every 28 days for up to 4 cycles.

16 weeks

Daily visits for 5 days, then weekly visits for 4 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then every 28 days for up to 1 year.

1 year

Follow-up visits every 28 days

Treatment Details

Interventions

• 8-Chloroadenosine
• Venetoclax

Trial Overview This phase I trial is testing the safety and optimal dosage of a new drug combo: 8-Chloroadenosine with Venetoclax. The goal is to see if this combination can block cancer growth in patients whose AML has returned after treatment or hasn't responded at all.

Participant Groups

Group I: Treatment (8-chloroadenosine, venetoclax) Experimental Treatment 2 Interventions

Patients receive 8-Cl-Ado IV over 4 hours daily on days 1-5 and venetoclax PO QD on days 1-28. Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a Phase 3 clinical trial, venetoclax combined with low-dose cytarabine showed improved response rates and overall survival in patients with newly diagnosed acute myeloid leukemia who couldn't undergo intensive chemotherapy, supporting its efficacy.

In an expanded access study in Japan involving 14 patients, the safety profile of venetoclax was consistent with previous findings, with neutropenia being the most common serious side effect, indicating that careful management of adverse events is crucial in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. Asada, N., Ando, J., Takada, S., et al.[2023]

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]

In a study of 211 patients with untreated acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, venetoclax combined with low-dose cytarabine (LDAC) showed a median overall survival of 8.4 months compared to 4.1 months for the placebo group, indicating a 30% reduction in the risk of death.

The treatment with venetoclax + LDAC also resulted in significantly higher complete response rates (48.3% vs. 13.2%) and improved event-free survival (4.9 months vs. 2.1 months), while maintaining a similar safety profile to the placebo group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). Wei, AH., Panayiotidis, P., Montesinos, P., et al.[2022]

In a phase 3 trial involving 211 adults with acute myeloid leukemia (AML) who were not eligible for intensive chemotherapy, the combination of venetoclax and low-dose cytarabine (LDAC) showed a clinically meaningful improvement in overall survival, with a median survival of 8.4 months compared to 4.1 months for LDAC alone.

The treatment also resulted in higher remission rates, with 48% of patients achieving complete remission or complete remission with incomplete blood count recovery, while maintaining a manageable safety profile, despite some significant adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Wei, AH., Montesinos, P., Ivanov, V., et al.[2021]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

8-chloroadenosine demonstrated significant anti-tumor activity in mice, achieving a 71.7% inhibition rate against hepatoma H22 and a life-prolonging effect of 124% in mice with ascitic leukemia L-1210, indicating its potential as an effective cancer treatment.

The compound also showed low toxicity, with LD50 values of 1025 mg/kg in mice and 793 mg/kg in rats, suggesting it could be a safer option for cancer therapy compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Antitumor activities of 8-chloroadenosine in vivo and in vitro]. Fang, J., Shi, Y., Zhang, L.[2017]

In a study involving patients with relapsed/refractory acute myeloid leukemia (AML), 8-chloro-adenosine (8-Cl-Ado) showed some effectiveness in reducing AML blasts in peripheral blood, but responses were temporary, indicating the need for combination therapies.

The treatment was associated with significant cardiac toxicity, necessitating careful monitoring for arrhythmias and QT interval changes, with a recommended phase 2 dose (RP2D) established at 400 mg/m2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 trial of 8-chloro-adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics. Pullarkat, V., Chen, LS., Palmer, J., et al.[2023]

8-Chloroadenosine (8-Cl-Ado) shows promising efficacy in inducing cell death in mantle cell lymphoma (MCL) cell lines, with significant mitochondrial dysfunction and reduced ATP levels observed after 24 hours of treatment.

The mechanism of action involves both DNA and RNA-directed effects, leading to decreased DNA synthesis and selective depletion of dATP pools, which may contribute to the inhibition of cell growth and promote apoptosis in MCL cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical activity of 8-chloroadenosine with mantle cell lymphoma: roles of energy depletion and inhibition of DNA and RNA synthesis. Dennison, JB., Balakrishnan, K., Gandhi, V.[2021]

8-chloro-adenosine (8-Cl-Ado) induces significant tumor cell death in breast cancer by activating the AMPK pathway, leading to autophagy, rather than primarily through apoptosis, as shown in cell line studies.

In vivo studies demonstrated that 8-Cl-Ado effectively inhibited tumor growth in mouse models, with some tumors showing no detectable presence after treatment, supporting its potential as a therapeutic option for breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATP directed agent, 8-chloro-adenosine, induces AMP activated protein kinase activity, leading to autophagic cell death in breast cancer cells. Stellrecht, CM., Vangapandu, HV., Le, XF., et al.[2023]

The new compound 8-chloro-adenosine-5'-O-stearate (8CAS) and its formulation in pegylated liposomes significantly improved the pharmacokinetic properties of 8-chloro-adenosine (8CA), increasing its elimination half-life and bioavailability in rats after intravenous administration.

8CAS and its pegylated liposomes retained cytotoxic effects against cancer cells, with no significant hematological toxicity observed in mice, suggesting a safer and more effective delivery method for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel approach to improve the pharmacokinetic properties of 8-chloro-adenosine by the dual combination of lipophilic derivatisation and liposome formulation. Jiao, YY., Wang, XQ., Lu, WL., et al.[2018]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

The combination of venetoclax with hypomethylating agents (HMA) has significantly improved survival rates in patients with acute myeloid leukemia (AML), as demonstrated in a phase 3 study.

Venetoclax is also safe when added to standard intensive regimens, leading to high remission rates and measurable residual disease negativity in both newly diagnosed and relapsed/refractory AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. Ball, BJ., Koller, PB., Pullarkat, V.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan. [2023]

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

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]

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

6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy (141/150). [2022]

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

Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

6. China pubmed.ncbi.nlm.nih.gov

[Antitumor activities of 8-chloroadenosine in vivo and in vitro]. [2017]

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

A phase 1 trial of 8-chloro-adenosine in relapsed/refractory acute myeloid leukemia: An evaluation of safety and pharmacokinetics. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Preclinical activity of 8-chloroadenosine with mantle cell lymphoma: roles of energy depletion and inhibition of DNA and RNA synthesis. [2021]

9. England pubmed.ncbi.nlm.nih.gov

ATP directed agent, 8-chloro-adenosine, induces AMP activated protein kinase activity, leading to autophagic cell death in breast cancer cells. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A novel approach to improve the pharmacokinetic properties of 8-chloro-adenosine by the dual combination of lipophilic derivatisation and liposome formulation. [2018]

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

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]

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

Venetoclax in combination with nucleoside analogs in acute myelogenous leukemia. [2023]