FP-045 for Fanconi Anemia

Recruiting at 5 trial locations

Overseen By Yisheng Lee, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Foresee Pharmaceuticals Co., Ltd.

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: Malignancy, Myelodysplastic syndrome, Leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Trial Summary

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you require a strong CYP3A4 inhibitor.

What data supports the idea that FP-045 for Fanconi Anemia is an effective drug?

The available research does not provide specific data on FP-045 for Fanconi Anemia. Instead, it discusses other treatments like eltrombopag, which has shown effectiveness in improving blood cell production in related conditions like aplastic anemia and myelodysplastic syndromes. Eltrombopag helped reduce the need for blood transfusions and improved blood cell counts in these conditions, suggesting it might be a promising alternative for treating Fanconi Anemia. ^{1 2 3 4 5}

What safety data exists for FP-045 (Mirivadelgat) in treating Fanconi Anemia?

The provided research does not contain any safety data specifically for FP-045, Mirivadelgat, or FP 045 in the treatment of Fanconi Anemia. The studies mentioned focus on other treatments and conditions, such as eltrombopag for Fanconi Anemia and myelodysplastic syndrome, ruxolitinib and jaktinib for myelofibrosis, and avatrombopag for chronic immune thrombocytopenia. Therefore, no relevant safety data for FP-045 is available in the provided research. ^{1 4 6 7 8}

Is the drug FP-045 a promising treatment for Fanconi Anemia?

The information provided does not include any details about FP-045 or its effectiveness for treating Fanconi Anemia. Therefore, we cannot determine if FP-045 is a promising treatment for this condition based on the given research articles. ^{9 10 11 12 13}

What is the purpose of this trial?

This is a multi-center, Phase 1/2 study to determine the Optimal Biologic Dose (OBD) and to evaluate the safety, tolerability, PK, and preliminary activity of FP 045 when administered orally in young adult/adolescent and pediatric patients with Fanconi anemia. The study will enroll a total of 4 young adult/adolescent patients and a minimum of 8 and up to 12 pediatric patients with mild-moderate bone marrow failure who have not undergone hematopoietic cell transplant. This makes the total patient number between 12-16 total. Dose escalation will occur individually for each patient, within each age group. Each patient will receive each of 3 dose levels of FP 045 (intra-patient dose escalation), beginning with Dose Level 1, followed by Dose Levels 2 and 3. Each dose level will be administered for 28 days prior to escalation to the next higher dose level for that patient.

Research Team

Susan Whitaker

Principal Investigator

Foresee Pharmaceuticals

Eligibility Criteria

This trial is for young people aged 3-25 with Fanconi anemia and mild to moderate bone marrow failure. Participants must not have had a transplant or certain medical conditions, including active infections or liver issues. They should use effective birth control if applicable.

Inclusion Criteria

Females of child-bearing potential and males required to use highly effective birth control

I am between 3 and 25 years old.

I have been diagnosed with Fanconi anemia through a specific genetic test.

Exclusion Criteria

I have had a bone marrow or stem cell transplant.

I have active Hepatitis B or C.

I am receiving treatment for active graft versus host disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive FP-045 at three escalating dose levels, each for 28 days, to determine the Maximum Tolerated Dose (MTD)

12 weeks

Weekly visits for safety assessments

Treatment Continuation

Participants continue treatment at the highest dose or individual MTD, transitioning to the Optimal Biologic Dose (OBD) for 3 months

3 months

Monthly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

3-6 months

Treatment Details

Interventions

• FP-045

Trial Overview The study tests FP-045, given orally in escalating doses over three stages, each lasting 28 days. It aims to find the best dose and assess safety, how the body processes the drug (PK), and its initial effectiveness in treating Fanconi anemia.

Participant Groups

Group I: FP-045 Experimental Treatment 1 Intervention

The study will enroll a total of 6 young adult/adolescent patients progressing through three dose levels, followed by a minimum of 8 and up to 12 pediatric patients progressing through up to three dose levels.

Who Is Running the Clinical Trial?

Foresee Pharmaceuticals Co., Ltd.

Lead Sponsor

Trials

15

Recruited

1,200+

Findings from Research

In a case of Fanconi anemia, the combination of eltrombopag and oxymetholone successfully induced trilineage hematopoiesis, which means it stimulated the production of red blood cells, white blood cells, and platelets.

This treatment eliminated the need for blood transfusions prior to hematopoietic stem cell transplant, potentially improving the patient's outcome after the transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trilineage Hematopoiesis Induced by Low-dose Eltrombopag in a Patient With Fanconi Anemia can be Used as a Bridge to Hematopoietic Stem Cell Transplant. Gupta, A., Palassery, R., Meyerson, H., et al.[2019]

In a phase II study involving 55 patients with severe aplastic anemia (SAA) who did not respond to standard treatments, hetrombopag demonstrated significant efficacy, with 41.8% of patients achieving a hematologic response by week 18.

Hetrombopag was found to be well-tolerated over a 52-week treatment period, with a durable 12-month relapse-free survival rate of 82.2%, although adverse events were common, with 50.9% of patients experiencing treatment-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter phase II study on the efficacy and safety of hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy. Peng, G., He, G., Chang, H., et al.[2022]

Eltrombopag's bioavailability is significantly reduced (by 59% for AUC and 65% for Cmax) when taken with a high-fat, high-calcium breakfast compared to a fasted state, indicating that food can greatly affect its absorption.

In contrast, low-calcium meals do not significantly alter eltrombopag's bioavailability, but taking it with an antacid containing aluminum and magnesium can decrease its systemic exposure by approximately 70%. Overall, eltrombopag was well tolerated with mild to moderate side effects reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies. Williams, DD., Peng, B., Bailey, CK., et al.[2016]

In a phase 2 study involving 25 patients with lower-risk myelodysplastic syndromes (MDS), Eltrombopag (EPAG) demonstrated a 44% response rate in improving blood cell counts, indicating its efficacy in restoring hematopoiesis.

EPAG was well-tolerated, with no patients discontinuing due to adverse events, although some experienced reversible liver toxicity; importantly, no patients progressed to acute myeloid leukemia (AML) during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome. Vicente, A., Patel, BA., Gutierrez-Rodrigues, F., et al.[2022]

Eltrombopag (EPAG) is a well-tolerated oral treatment that shows promising efficacy in patients with moderate aplastic anemia (MAA) and uni-lineage cytopenias (UC), with 17 out of 34 patients responding positively after treatment.

The study demonstrated that EPAG can lead to significant improvements in blood counts, with 12 patients maintaining stable counts for a median of 8 months before needing re-initiation of treatment, and no significant increase in cancer-related mutations was observed during the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias. Fan, X., Desmond, R., Winkler, T., et al.[2022]

In a 6-month Phase 3 study involving 49 adults with chronic immune thrombocytopenia (ITP), avatrombopag (20 mg/day) significantly improved platelet counts compared to placebo, with a median cumulative number of weeks of platelet response of 12.4 weeks versus 0 weeks for placebo (P < 0.0001).

Avatrombopag also demonstrated a higher platelet response rate at day 8 (65.63% vs. 0.0% for placebo, P < 0.0001) and reduced the need for concomitant ITP medications, while maintaining a safety profile similar to earlier studies, with common side effects being headache and contusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Jurczak, W., Chojnowski, K., Mayer, J., et al.[2019]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

In a phase 2 trial involving 51 patients with myelofibrosis who were intolerant to ruxolitinib, 43.2% of those treated with the novel JAK inhibitor jaktinib showed a significant reduction in spleen volume after 24 weeks.

Jaktinib also improved symptoms related to myelofibrosis, with 61.8% of patients experiencing a notable decrease in total symptom scores, although it was associated with some serious adverse events, including anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are intolerant to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. Zhang, Y., Zhou, H., Duan, M., et al.[2023]

Tipifarnib, a farnesyl transferase inhibitor, effectively inhibits the growth of erythroid burst-forming units (BFU-E) in patients with polycythemia vera (PV), suggesting it could be a promising treatment option.

At low concentrations, tipifarnib specifically targets PV progenitor cells without affecting normal progenitors, indicating its potential for safer treatment with reduced risk of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells. Larghero, J., Gervais, N., Cassinat, B., et al.[2021]

In a phase 2 trial involving 34 patients with myelofibrosis who did not respond to ruxolitinib, 32.4% achieved a significant reduction in spleen volume after 24 weeks of treatment with jaktinib, indicating its potential efficacy for ruxolitinib-refractory patients.

Jaktinib also improved hemoglobin levels in 50% of transfusion-independent patients with low baseline hemoglobin and reduced overall symptoms in 46.4% of patients, although it was associated with notable adverse events like thrombocytopenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are relapsed or refractory to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. Zhang, Y., Zhang, Q., Liu, Q., et al.[2023]

Pacritinib, particularly at a dose of 200 mg twice per day, showed significant efficacy in treating advanced myelofibrosis in patients who were intolerant or resistant to ruxolitinib, with a spleen volume response rate of 9.3%.

The study demonstrated an acceptable safety profile for pacritinib, with no increase in severe hemorrhagic or cardiac events at the highest dose, making it a promising option for patients with severe thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. Gerds, AT., Savona, MR., Scott, BL., et al.[2021]

In a study involving 536 myelofibrosis patients, pacritinib demonstrated superior efficacy in reducing spleen size and improving symptoms compared to best available therapy, particularly in patients with low or absent JAK2V617F allele burden.

Pacritinib was effective across all JAK2V617F allele burden quartiles, showing significant spleen response rates in patients with low allele burden (0%-25% and 25%-50%), while no responses were observed in the best available therapy group for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden. Tremblay, D., Mesa, R., Scott, B., et al.[2022]

The study reveals that phosphatidyl inositol 4,5-bisphosphate (PI(4,5)P2) localizes at the leading edge of neutrophil-like HL-60 cells, similar to phosphatidyl inositol 3,4,5-trisphosphate (PI(3,4,5)P3), challenging previous assumptions about its distribution.

The enzymes responsible for producing PI(4,5)P2, PI5KIalpha and PI5KIgamma, also localize at the leading edge, suggesting that the regulation of PI(3,4,5)P3 polarization involves more than just the actions of PI3K and PTEN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunostaining evidence for PI(4,5)P2 localization at the leading edge of chemoattractant-stimulated HL-60 cells. Sharma, VP., DesMarais, V., Sumners, C., et al.[2021]

References

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

Trilineage Hematopoiesis Induced by Low-dose Eltrombopag in a Patient With Fanconi Anemia can be Used as a Bridge to Hematopoietic Stem Cell Transplant. [2019]

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

A multicenter phase II study on the efficacy and safety of hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy. [2022]

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

Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies. [2016]

4. Italy pubmed.ncbi.nlm.nih.gov

Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndrome. [2022]

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

Eltrombopag for patients with moderate aplastic anemia or uni-lineage cytopenias. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. [2019]

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

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. [2023]

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

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are intolerant to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. [2023]

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

Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells. [2021]

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

Safety and efficacy of jaktinib (a novel JAK inhibitor) in patients with myelofibrosis who are relapsed or refractory to ruxolitinib: A single-arm, open-label, phase 2, multicenter study. [2023]

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

Determining the recommended dose of pacritinib: results from the PAC203 dose-finding trial in advanced myelofibrosis. [2021]

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

Pacritinib demonstrates spleen volume reduction in patients with myelofibrosis independent of JAK2V617F allele burden. [2022]

13. England pubmed.ncbi.nlm.nih.gov

Immunostaining evidence for PI(4,5)P2 localization at the leading edge of chemoattractant-stimulated HL-60 cells. [2021]