Pacritinib + Azacitidine for Leukemia

Overseen By Katherine Vandris

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Douglas Tremblay

Must not be taking: CYP3A4 inhibitors, CYP450 inducers

Disqualifiers: Active GVHD, Serious infection, Others

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

Compensation: Varies

Number of Visits: Unknown

26 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 1/2 trial of pacritinib in combination with azacitidine in patients with Chronic Myelomonocytic Leukemia (CMML). Patients will be newly diagnosed or previously treated but could not have received a prior JAK inhibitor. Patients who have previously been treated with a hypomethylating agent (HMA) must have received ≤ 1 cycle. Pacritinib will be initially tested at a dose of 200mg twice daily (dose level 0) in combination with azacitidine 75mg/m2, which can be administered subcutaneously or intravenously, for 7 days in a 28-day cycle. If there are 2 DLTs in the first 6 patients, there will be a dose escalation to pacritinib 100mg twice daily (dose level -1) and an additional 6 patients will be enrolled. Based on the phase 1, 3+3 dose de-escalation design, 6-12 patients will be enrolled in the phase 1 portion. After the completion of phase 1 and identification of the recommended phase 2 dose (RP2D), the trial will then proceed to phase 2 which will employ a Simon two stage design. This portion will include the 6 patients enrolled during the phase 1 portion at the MTD. An interim analysis for futility will occur. If 3 or fewer patients have had a clinical benefit (CB) or better, as defined by 2015 MDS/MPN IWG criteria, the PI and DSMC will meet to discuss the totality of the evidence and determine if the trial shall proceed. In the second stage, an additional 12 patients will be enrolled.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as strong CYP3A4 inhibitors or strong CYP450 inducers, at least 14 days before starting the trial. Additionally, you must stop any medications that increase the risk of bleeding, like certain blood thinners, 14 days before the trial begins.

What data supports the effectiveness of the drug Azacitidine for leukemia?

Azacitidine is shown to significantly prolong survival in patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) compared to conventional care, and it is associated with a lower risk of AML progression and higher rates of remission and blood cell improvement. ^{1 2 3 4 5}

How is the drug Pacritinib + Azacitidine unique for treating leukemia?

Pacritinib + Azacitidine is unique because it combines two drugs: Pacritinib, which is a targeted therapy that inhibits specific proteins involved in cancer cell growth, and Azacitidine, which is already used to treat certain blood cancers by affecting the DNA of cancer cells. This combination may offer a novel approach by potentially enhancing the effectiveness of treatment compared to using Azacitidine alone. ^{1 2 3 4 6}

Research Team

Douglas Tremblay, MD

Principal Investigator

Icahn School of Medicine

Eligibility Criteria

Adults diagnosed with Chronic Myelomonocytic Leukemia (CMML) who haven't taken JAK inhibitors and have had at most one cycle of hypomethylating agents. They should be in a specific risk category, have a life expectancy over 24 weeks, and an ECOG status ≤3. Participants must not have certain other health conditions or recent treatments that could interfere with the study.

Inclusion Criteria

Participants must have a life expectancy of at least 24 weeks per investigator.

Females of reproductive potential should use effective contraception during treatment with azacitidine and for 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the last dose.

I have never taken JAK inhibitor medications.

Exclusion Criteria

If a patient is identified to have COVID-19 during the screening period, participants may be considered eligible if in the opinion of the investigator there are no COVID-19 sequlae that may place the patient at a higher risk of receiving investigational treatment.

I do not have uncontrolled HIV.

I have not had serious heart problems in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Pacritinib is tested at a dose of 200mg twice daily in combination with azacitidine 75mg/m2 for 7 days in a 28-day cycle. Dose escalation to pacritinib 100mg twice daily if needed.

up to 6 cycles (each cycle is 28 days)

Treatment Phase 2

Continuation of treatment with the recommended phase 2 dose (RP2D) using a Simon two-stage design. Includes interim analysis for futility.

up to 6 cycles (each cycle is 28 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and overall survival.

up to 24 months

Treatment Details

Interventions

• Azacitidine
• Pacritinib

Trial Overview The trial is testing pacritinib combined with azacitidine on CMML patients. It starts with phase 1 to find the safest dose level, followed by phase 2 to assess effectiveness using criteria from the MDS/MPN IWG. The treatment involves taking pacritinib twice daily and azacitidine for seven days every four-week cycle.

Participant Groups

Group I: Pacritinib in combination with Azacitidine Experimental Treatment 2 Interventions

Participants will take pacritinib 200 mg BID for each 28 day cycle, azacitidine 75mg/m2 will be administered IV or SQ QD D1-7 of each 28 day cycle

Azacitidine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Douglas Tremblay

Lead Sponsor

Trials

1

Recruited

30+

Sobi, Inc.

Industry Sponsor

Trials

14

Recruited

1,000+

Findings from Research

The Vidaza Access Program in Belgium successfully facilitated access to azacitidine treatment for 175 patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) by streamlining the approval process for patient dossiers.

Out of the 175 patient dossiers submitted, 163 were approved by Celgene, demonstrating the program's effectiveness in ensuring timely treatment initiation without financial risk to hospitals, which is crucial for patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. Meers, S., Selleslag, D., Potier, H., et al.[2018]

Azacitidine (Vidaza) has received approval for the treatment of juvenile myelomonocytic leukemia, a rare blood cancer primarily affecting children under the age of four.

This approval highlights the drug's potential efficacy in addressing a specific and challenging pediatric cancer, providing a new treatment option for affected children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug Receives New Indication for Juvenile Myelomonocytic Leukemia. Aschenbrenner, DS.[2022]

In a study of 149 patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML), azacitidine treatment resulted in a median progression-free survival (PFS) of 10.9 months and an overall survival (OS) of 14.1 months, demonstrating its effectiveness in a real-world clinical setting.

The safety profile of azacitidine was consistent with previous clinical trials, and factors such as Eastern Cooperative Oncology Group (ECOG) performance status and red blood cell transfusion prior to treatment were identified as predictive factors for better PFS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). Wehmeyer, J., Zaiss, M., Losem, C., et al.[2019]

In a real-life study of 49 patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), azacitidine demonstrated a clinically acceptable safety profile, with 67.3% of patients experiencing treatment-related adverse events.

Efficacy results showed that 41.4% of MDS and CMML patients achieved a complete or partial response, and 43.8% of transfusion-dependent patients became transfusion-independent, with a median overall survival of 490 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. Beguin, Y., Selleslag, D., Meers, S., et al.[2015]

Azacitidine (Vidaza) is the only drug approved in the EU that significantly prolongs survival in adults with high-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), making it a crucial treatment option for patients not eligible for stem cell transplantation.

The treatment is associated with a lower risk of AML progression and higher rates of remission and blood transfusion independence, while maintaining an acceptable safety profile, with peripheral cytopenias being the most common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. Keating, GM.[2021]

Histone deacetylase inhibitors (HDACi) like trichostatin A (TSA) and valproic acid (VPA) significantly enhance the effectiveness of etoposide in inducing apoptosis in HL60 leukemia cells, indicating a potential for improved cancer treatment strategies.

The synergistic effect of combining HDACi with etoposide on apoptosis is cell-type dependent, as similar results were not observed in U937 cells, highlighting the importance of considering specific cancer characteristics in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of histone deacetylase inhibitors trichostatin A and valproic acid on etoposide-induced apoptosis in leukemia cells. Jasek, E., Lis, GJ., Jasinska, M., et al.[2013]

References

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

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia. [2018]

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

Drug Receives New Indication for Juvenile Myelomonocytic Leukemia. [2022]

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

Impact of performance status and transfusion dependency on outcome of patients with myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia treated with azacitidine (PIAZA study). [2019]

4. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey. [2015]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. [2021]

6. Greece pubmed.ncbi.nlm.nih.gov

Effect of histone deacetylase inhibitors trichostatin A and valproic acid on etoposide-induced apoptosis in leukemia cells. [2013]