Tolinapant + Decitabine/Cedazuridine for Peripheral T-Cell Lymphoma

Recruiting at 49 trial locations

Overseen By Astex Pharmaceuticals, Inc.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Taiho Oncology, Inc.

Must not be taking: CYP3A4 inhibitors/inducers

Disqualifiers: Cardiac disease, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

33 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary purpose of the study is to assess safety, and to identify the recommended phase 2 dose (RP2D) of tolinapant in combination with oral decitabine/cedazuridine in Phase 1 and to assess preliminary efficacy as determined by overall response rate (ORR) in Phase 2.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot use certain medications like CYP3A4 inhibitors/inducers within 2 weeks of starting the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What data supports the effectiveness of the drug Tolinapant + Decitabine/Cedazuridine for Peripheral T-Cell Lymphoma?

Research shows that decitabine, a component of the treatment, has been effective in treating other blood cancers like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with significant improvements in survival and response rates. Additionally, decitabine has shown potential when combined with other agents in treating peripheral T-cell lymphoma, suggesting it could be beneficial in this new combination. ^{1 2 3 4 5}

What safety data exists for Tolinapant + Decitabine/Cedazuridine treatment?

The combination of decitabine and cedazuridine has been studied for safety in conditions like myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Common serious side effects included low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and fever with low white blood cell counts (febrile neutropenia). ^{1 2 3 6 7}

What makes the drug Tolinapant + Decitabine/Cedazuridine unique for treating Peripheral T-Cell Lymphoma?

This drug combination is unique because it combines Tolinapant, which may enhance the effectiveness of other cancer treatments, with Decitabine/Cedazuridine, an oral formulation that increases the bioavailability of Decitabine, a DNA methyltransferase inhibitor. This combination could potentially offer a more effective and convenient oral treatment option for Peripheral T-Cell Lymphoma, a condition with limited standard treatments. ^{1 2 3 8 9}

Eligibility Criteria

This trial is for people with a specific type of cancer called Peripheral T-cell Lymphoma (PTCL) that has come back or didn't respond to treatment. They should have tried at least two treatments before, be expected to live more than 12 weeks, and not be pregnant or breastfeeding. They can't join if they've had certain heart problems, uncontrolled infections, significant mental illness or substance abuse issues, other active cancers needing treatment (except some breast/prostate/bladder cancers), recent other cancer treatments like chemotherapy or CAR-T therapy within specified time frames, known HIV/HBV/HCV infection, CNS lymphoma history, allogeneic transplant history or autotransplant within the last 100 days.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

My cancer is a type of T-cell lymphoma confirmed by tests.

I am not pregnant or breastfeeding and my pregnancy test was negative.

Exclusion Criteria

I have a history of heart problems or am at risk for them.

I have been diagnosed with lymphoma in my central nervous system.

Known significant mental illness or active substance abuse

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Participants receive tolinapant in combination with oral decitabine/cedazuridine to determine the recommended phase 2 dose (RP2D)

28-day cycles

Visits as per cycle schedule

Phase 2 Treatment

Participants receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine

28-day cycles

Visits as per cycle schedule

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 54 months

Treatment Details

Interventions

• Decitabine + Cedazuridine
• Tolinapant

Trial Overview The study is testing how safe and effective a drug named Tolinapant is when given with an oral combination of Decitabine/Cedazuridine in patients with PTCL. The first phase will find the best dose to use while checking safety; the second phase will see how well it works by measuring response rates.

Participant Groups

Group I: Phases 1 and 2: Tolinapant + Oral Decitabine/Cedazuridine Experimental Treatment 2 Interventions

Tolinapant, orally, once daily (QD) on Days 1 to 7 and 15 to 21 of each 28-day cycle in combination with oral decitabine/cedazuridine fixed-dose combination (FDC) tablet, QD on days determined by the Lead-in Phase during each 28-day cycle. The starting dose of tolinapant will be escalated stepwise in successive cohorts until the RP2D is determined. Based on RP2D and results determined from Phase 1 participants would receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine, FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle in Phase 2.

Group II: Phase 1: Oral Decitabine/Cedazuridine Experimental Treatment 1 Intervention

Decitabine/cedazuridine FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle.

Who Is Running the Clinical Trial?

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Astex Pharmaceuticals, Inc.

Lead Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

The phase 2 study found that oral cedazuridine/decitabine (100 mg/35 mg) provided similar systemic exposure and DNA demethylation compared to standard IV decitabine (20 mg/m2) in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia, indicating comparable efficacy.

Clinical responses were observed in 60% of patients, with 21% achieving a complete response, while the most common serious side effects included neutropenia (46%) and thrombocytopenia (38%), highlighting the treatment's safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Garcia-Manero, G., Griffiths, EA., Steensma, DP., et al.[2021]

The fixed-dose oral combination of decitabine and cedazuridine (Inqovi®) has been approved for treating myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), enhancing the oral bioavailability of decitabine through the inhibition of cytidine deaminase by cedazuridine.

Decitabine is already an established treatment for MDS and CMML, and the combination therapy has shown promise in ongoing clinical studies for other cancers like acute myeloid leukaemia (AML), glioma, and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine/Cedazuridine: First Approval. Dhillon, S.[2021]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

Oral azacitidine (CC-486) has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia who are in complete remission, highlighting its efficacy in this specific patient population.

The combination of decitabine and cedazuridine (ASTX727) is approved for treating adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia, particularly those with intermediate-1 or higher risk, indicating its targeted therapeutic application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Kipp, D., H Wei, A.[2022]

References

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

Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]

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

Integrated clinical and genomic evaluation of guadecitabine (SGI-110) in peripheral T-cell lymphoma. [2023]

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

Decitabine/Cedazuridine: First Approval. [2021]

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

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

5. Italy pubmed.ncbi.nlm.nih.gov

Histone modifier gene mutations in peripheral T-cell lymphoma not otherwise specified. [2019]

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

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]

7. England pubmed.ncbi.nlm.nih.gov

The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma. [2023]

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

Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5-aza-2'-deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method. [2022]