Pacritinib + Talazoparib for Myeloproliferative Disorders

Overseen By Abigail Protocol Development Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fox Chase Cancer Center

Must be taking: JAK2 inhibitors

Must not be taking: Investigational agents, Antiretrovirals

Disqualifiers: Acute myeloid leukemia, Uncontrolled illness, others

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

Compensation: Varies

Number of Visits: 5

Duration: 28 days per cycle

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective phase I dose-escalation study, with the primary objective to access the MTD and find the RP2D of talazoparib, given in combination with standard of care dosing of pacritinib.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on other investigational drugs. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Talazoparib?

Talazoparib has shown effectiveness in treating advanced breast cancer with specific genetic mutations, improving progression-free survival compared to chemotherapy. It also demonstrated antitumor activity in prostate cancer with certain DNA repair alterations. ^{1 2 3 4 5}

Is the combination of Pacritinib and Talazoparib safe for humans?

Talazoparib has been studied in patients with advanced breast cancer and other solid tumors, showing some side effects like fatigue, low blood cell counts, and anemia. These studies suggest that while Talazoparib can be effective, it may also cause significant side effects, especially in people with certain genetic mutations. ^{1 4 6 7 8}

How is the drug combination of Pacritinib and Talazoparib unique for treating myeloproliferative disorders?

This drug combination is unique because it combines Pacritinib, which is a kinase inhibitor, with Talazoparib, a PARP inhibitor that helps prevent cancer cells from repairing their DNA, potentially offering a novel approach to treating myeloproliferative disorders by targeting different pathways involved in cancer cell survival. ^{1 2 3 9 10}

Research Team

Peter Abdelmessieh, DO, MSc

Principal Investigator

Fox Chase Cancer Center

Eligibility Criteria

This trial is for adults over 18 with certain types of blood disorders like myelofibrosis or chronic leukemia, who've had symptoms measured by the MFSAF v4.0 and are considered intermediate-2/high-risk. They must have tried a JAK2 inhibitor treatment without success and have good organ function. Pregnant women, those with uncontrolled illnesses, recent other cancers, or severe unresolved treatment side effects can't join.

Inclusion Criteria

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

My organs are functioning normally.

My myelofibrosis is classified as intermediate-2 or high-risk.

Exclusion Criteria

Pregnant or breast-feeding

My side effects from previous treatments are mild, except for possible nerve pain, hair loss, and tiredness.

I don't have any serious illnesses or conditions that would stop me from following the study's requirements.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lead-in Phase

Pacritinib is initiated on day -7 with a standard of care dose of 200mg twice daily

1 week

1 visit (in-person)

Treatment

Talazoparib is administered in combination with pacritinib, with dose escalation to determine the maximum tolerated dose

28 days per cycle

4 visits (in-person) per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pacritinib
• Talazoparib

Trial Overview The study tests different doses of Talazoparib combined with standard pacritinib to find the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). It's a phase I trial where patients receive escalating doses to assess safety and effectiveness in treating myeloproliferative neoplasms resistant to JAK2 inhibitors.

Participant Groups

Group I: Dose Level 4 Experimental Treatment 2 Interventions

1 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)

Group II: Dose Level 3 Experimental Treatment 2 Interventions

0.75 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)

Group III: Dose Level 2 Experimental Treatment 2 Interventions

0.5 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)

Group IV: Dose Level 1 Experimental Treatment 2 Interventions

0.25 mg (PO, QD) Talazoparib (Days 1-14) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)

Group V: Dose Level -1 Experimental Treatment 2 Interventions

0.25 mg (PO, QD) Talazoparib (Days 1-7) 200 mg (PO, BID) Pacritinib (Day 1-28, Lead in dosing of Pacritinib day -7 for the first cycle of treatment)

Pacritinib is already approved in United States for the following indications:

Approved in United States as Vonjo for:

• Intermediate or high-risk primary or secondary myelofibrosis with platelet counts below 50 × 10^9/L

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

Findings from Research

Talazoparib is an oral PARP inhibitor recently approved in the USA for treating adults with specific types of breast cancer, particularly those with BRCA mutations, highlighting its targeted efficacy in a defined patient population.

The drug is also being explored for use in other cancers, including metastatic castration-resistant prostate cancer and early triple negative breast cancer, indicating its potential versatility in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib: First Global Approval. Hoy, SM.[2020]

In a phase Ib trial involving 22 patients with metastatic pancreatic ductal adenocarcinoma, combinations of avelumab or talazoparib with binimetinib showed higher-than-expected rates of dose-limiting toxicity (DLT), particularly at the 45 mg dose, leading to dose adjustments.

Despite the safety concerns, the overall safety profiles of the combinations were consistent with those of the individual drugs, but no objective tumor responses were observed in the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. Rodon Ahnert, J., Tan, DS., Garrido-Laguna, I., et al.[2023]

In the TALAPRO-1 study involving 97 men with metastatic castration-resistant prostate cancer (mCRPC), talazoparib significantly improved health-related quality of life (HRQoL) and reduced pain levels, particularly in patients with BRCA1/2 mutations.

The study found that 84% of all patients and 83% of those with BRCA1/2 mutations did not experience a deterioration in worst pain after 12 months of treatment, indicating a high probability of maintaining pain relief while receiving talazoparib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1. Saad, F., de Bono, J., Barthélémy, P., et al.[2023]

In the ABRAZO study, talazoparib (1 mg/day) maintained global health status and quality of life (GHS/QoL) in patients with advanced breast cancer, with median time to deterioration of GHS/QoL being 2.8 months for those with prior platinum therapy and 5.5 months for those with multiple cytotoxic regimens.

Patients reported significant improvements in breast and arm symptoms, as well as their future perspective, despite some deterioration in role functioning and dyspnoea symptoms, indicating that talazoparib can provide meaningful benefits in symptom management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial. Hurvitz, SA., Quek, RGW., Turner, NC., et al.[2021]

In the EMBRACA trial involving 431 patients with gBRCA1/2-mutated advanced breast cancer, talazoparib did not significantly improve overall survival compared to chemotherapy, with a hazard ratio of 0.848 (P = 0.17).

However, talazoparib showed a significant advantage in improving patient-reported outcomes and delaying deterioration in quality of life and breast symptoms, indicating its potential benefits beyond survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. Litton, JK., Hurvitz, SA., Mina, LA., et al.[2023]

In a phase I study involving 24 patients with solid tumors, the combination of the PARP inhibitor talazoparib and carboplatin showed efficacy, particularly in patients with germline BRCA1/2 mutations, resulting in one complete and two partial responses.

However, the treatment was associated with significant hematologic toxicity, especially in gBRCA carriers, highlighting the need for an intermittent dosing schedule of talazoparib to improve the safety and effectiveness of the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Toxicity in Patients with and without DNA Repair Mutations: Phase I Study of Carboplatin and Talazoparib in Advanced Solid Tumors. Dhawan, MS., Bartelink, IH., Aggarwal, RR., et al.[2018]

In a phase III study involving 431 patients with advanced breast cancer and BRCA1/2 mutations, talazoparib significantly improved progression-free survival compared to physician's choice of chemotherapy, with hazard ratios indicating a 53% to 40% reduction in the risk of disease progression for different subgroups.

Talazoparib also showed higher objective response rates and clinical benefit rates across all subgroups, along with consistent improvements in patient-reported outcomes, while common side effects included anemia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in Clinically Relevant Patient Subgroups From the EMBRACA Study: Talazoparib vs Physician's Choice Standard-of-Care Chemotherapy. Rugo, HS., Ettl, J., Hurvitz, SA., et al.[2022]

In a phase 3 trial involving 431 patients with advanced breast cancer and BRCA1/2 mutations, talazoparib significantly improved progression-free survival compared to standard therapies, with a median of 8.6 months versus 5.6 months.

Talazoparib also demonstrated a higher objective response rate (62.6% vs. 27.2%) and better patient-reported outcomes, although it was associated with a higher incidence of hematologic adverse events, primarily anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. Litton, JK., Rugo, HS., Ettl, J., et al.[2023]

In a Phase I trial involving 33 patients with advanced hematologic malignancies, talazoparib was found to be relatively well tolerated, with the maximum tolerated dose (MTD) being 2.0 mg/day for acute myeloid leukemia and 0.9 mg/day for chronic lymphocytic leukemia.

The treatment demonstrated preliminary anti-leukemic activity, with 54.5% of patients achieving stable disease, indicating potential effectiveness in managing these types of cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I trial of talazoparib in patients with advanced hematologic malignancies. Gopal, AK., Popat, R., Mattison, RJ., et al.[2022]

In this study of melanoma cells and healthy fibroblasts, the PARP inhibitors talazoparib and niraparib, when combined with ionizing radiation, significantly increased cell death and caused G2/M cell cycle arrest, particularly in melanoma cells, which are homologous recombination deficient.

While the combination treatment shows potential, the effects vary between different melanoma cell lines, indicating that individual responses should be evaluated before recommending this therapy for broader use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts. Weigert, V., Jost, T., Hecht, M., et al.[2021]

References

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

Talazoparib: First Global Approval. [2020]

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

Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1. [2023]

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

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial. [2021]

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

Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial. [2023]

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

Differential Toxicity in Patients with and without DNA Repair Mutations: Phase I Study of Carboplatin and Talazoparib in Advanced Solid Tumors. [2018]

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

Outcomes in Clinically Relevant Patient Subgroups From the EMBRACA Study: Talazoparib vs Physician's Choice Standard-of-Care Chemotherapy. [2022]

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

Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. [2023]

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

A Phase I trial of talazoparib in patients with advanced hematologic malignancies. [2022]

10. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts. [2021]