Fadraciclib for Cancer

Recruiting at3 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Cyclacel Pharmaceuticals, Inc.

Must not be taking: Chemotherapy, Immunotherapy, others

Disqualifiers: Brain metastases, Cardiac disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests a new oral drug, Fadraciclib, for patients with advanced cancers or lymphomas who have no other treatment options. The drug works by blocking proteins that help cancer cells grow.

Do I need to stop my current medications to join the trial?

The trial requires that you stop certain treatments like chemotherapy, biologic therapy, and others at least 3 weeks before starting the study drug. The protocol does not specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Fadraciclib (CYC-065, CYC065) for cancer?

Fadraciclib is a cyclin-dependent kinase (CDK) inhibitor, similar to other CDK inhibitors like abemaciclib and dinaciclib, which have shown effectiveness in treating certain types of breast cancer by blocking proteins that help cancer cells grow. This suggests that Fadraciclib might also be effective in treating cancers by targeting similar pathways. ^{1 2 3 4 5}

What safety data is available for Fadraciclib (CYC-065) in humans?

Fadraciclib, also known as CYC-065, is a cyclin-dependent kinase (CDK) inhibitor, similar to other CDK4/6 inhibitors used in cancer treatment. These inhibitors have been associated with some serious side effects, including cardiovascular issues like heart failure and blood-related problems such as low white blood cell counts. However, many patients recover from these side effects, and ongoing research aims to better understand and manage these risks. ^{6 7 8 9 10}

What makes the drug Fadraciclib unique for cancer treatment?

Fadraciclib (CYC-065) is unique because it targets specific proteins involved in cancer cell growth and division, potentially offering a novel approach compared to standard treatments. It may work differently by inhibiting cyclin-dependent kinases, which are crucial for cancer cell proliferation. ^{11 12 13 14 15}

Research Team

Mark H Kirschbaum, MD

Principal Investigator

Cyclacel Pharmaceuticals, Inc.

Eligibility Criteria

Adults (18+) with advanced solid tumors or lymphoma, who've tried all standard treatments without success or have no standard options available. They must be able to take oral medication, have a performance status indicating they can carry out daily activities with ease or some limitation, and agree to use birth control if there's any chance of conception.

Inclusion Criteria

For Phase 1, all tumor types may be enrolled. For Phase 2, subjects will be enrolled as per the study design section above

Able to agree to and sign the informed consent and to comply with the protocol.

My advanced cancer has worsened despite standard treatments, or I can't tolerate them.

Exclusion Criteria

I have HIV with an uncontrolled viral load and take medication that could affect metabolism.

I have active hepatitis B or C.

I have an ongoing inflammatory bowel condition or had a GI perforation recently.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Dose escalation and dose-finding component with Fadraciclib administered orally in escalating doses starting at 50mg bid MWF for 3 weeks of a 4 week cycle

4 weeks per cycle

Phase 2 Treatment

Recommended Fadraciclib phase 2 dose and schedule administered orally in 28 day cycles

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Fadraciclib (Cyclin-Dependent Kinase (CDK) Inhibitor)

Trial Overview The trial is testing Fadraciclib, an oral drug taken twice daily. It's in early stages (phase 1/2) to see how safe it is and how well it works for cancer that has worsened despite treatment. The study will also look at how the body processes the drug and its effects on tumor biology.

Participant Groups

Group I: Phase I Dose escalation Experimental Treatment 1 Intervention

Phase I = Fadraciclib administered orally in escalating doses starting at 50mg bid MWF for 3 weeks of a 4 week cycle. Subsequent cohorts will escalate in dose and schedule until optimized phase 2 dose and schedule is achieved. Phase 2 = Recommended Fadraciclib phase 2 dose and schedule administered orally in 28 day cycles.

Who Is Running the Clinical Trial?

Cyclacel Pharmaceuticals, Inc.

Lead Sponsor

Trials

20

Recruited

2,100+

Findings from Research

In a phase II trial involving 30 patients with previously treated advanced breast cancer, dinaciclib showed some antitumor activity but was less effective than capecitabine, leading to the trial's early termination.

Dinaciclib was generally well-tolerated, but common severe side effects included neutropenia and leukopenia, indicating that while it has potential, its safety profile needs careful consideration in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Mita, MM., Joy, AA., Mita, A., et al.[2021]

Abemaciclib, when added to standard endocrine therapy, significantly reduces the risk of invasive disease and distant recurrence in high-risk early breast cancer patients, showing a 30% reduction in risk and improved invasive disease-free survival at 15.5 months and 27 months.

Over 80% of patients experienced diarrhea as a side effect, highlighting the need for monitoring and management of this adverse effect during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer. Raheem, F., Ofori, H., Simpson, L., et al.[2022]

CDK4/6 inhibitors are now standard treatments for hormone receptor-positive breast cancer, showing significant biological effects on cancer cells and influencing treatment outcomes.

The review discusses not only the mechanisms of resistance to these inhibitors but also potential combinatorial treatment strategies and biomarkers that could guide future clinical trials beyond breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective CDK4/6 Inhibitors: Biologic Outcomes, Determinants of Sensitivity, Mechanisms of Resistance, Combinatorial Approaches, and Pharmacodynamic Biomarkers. Knudsen, ES., Shapiro, GI., Keyomarsi, K.[2021]

In the FLIPPER trial, the combination of palbociclib and fulvestrant significantly improved progression-free survival (PFS) in postmenopausal women with HR+/HER2- advanced breast cancer compared to placebo and fulvestrant.

Patient-reported outcomes indicated that while global health status and quality of life (QoL) were maintained during treatment with palbociclib/fulvestrant, the time to deterioration in QoL was longer with placebo/fulvestrant, suggesting that palbociclib/fulvestrant is a beneficial treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. Tibau, A., Martínez, MT., Ramos, M., et al.[2023]

In a meta-analysis of 1,332 patients across 7 randomized trials, CDK4/6 inhibitors like palbociclib and ribociclib showed a high incidence of grade 3/4 neutropenia at 61%, but serious adverse effects were generally well tolerated with a low risk of treatment-related deaths (0%).

While serious adverse effects varied significantly among studies, the overall safety profile indicates that CDK4/6 inhibitors are associated with manageable side effects, particularly with rare occurrences of neutropenic fever (1%) and infections (3%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: Palbociclib and ribociclib. Costa, R., Costa, RB., Talamantes, SM., et al.[2022]

A meta-analysis of 53 Phase II/III/IV trials involving nearly 20,000 patients revealed that molecular target anticancer drugs significantly increase the risk of serious adverse events (SAEs) by 57% and fatal adverse events (FAEs) by 51% compared to placebo.

The overall incidence rates for SAEs and FAEs were found to be 26.9% and 2.3%, respectively, highlighting the need for careful monitoring and preventive measures for patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. Wang, Z., Yang, X., Wang, J., et al.[2020]

In a study of 1376 patients treated with CDK4/6 inhibitors for hormone receptor-positive metastatic breast cancer, cardiovascular adverse events (CVAEs) occurred in 24% of patients, indicating a notable risk associated with these therapies.

Patients who developed atrial fibrillation or heart failure while on CDK4/6 inhibitors had significantly higher all-cause death rates, with adjusted hazard ratios of 4.89 and 5.88, respectively, highlighting the need for careful cardiovascular monitoring in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Cardiovascular Events Associated With Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Metastatic Breast Cancer. Fradley, MG., Nguyen, NHK., Madnick, D., et al.[2023]

Overexpression of the p185ErbB2 receptor in breast cancer cells leads to resistance against Taxol by inhibiting the apoptosis process, which is crucial for cancer cell death.

The mechanism involves the upregulation of p21Cip1, which interferes with the activation of p34Cdc2 kinase, delaying cell cycle progression and preventing Taxol from inducing apoptosis, highlighting a potential target for overcoming drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase. Yu, D., Jing, T., Liu, B., et al.[2022]

The FAK inhibitor PND-1186 effectively blocks tumor growth and metastasis in mouse models of breast cancer, demonstrating significant anti-tumor efficacy when administered both intraperitoneally and orally.

PND-1186 not only inhibits FAK phosphorylation but also reduces inflammatory cytokine expression, suggesting it may impact tumor progression through effects on both cancer cells and the surrounding stromal environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Walsh, C., Tanjoni, I., Uryu, S., et al.[2022]

The small molecule FAK inhibitor Y15 effectively reduces colon cancer cell growth and promotes apoptosis in vitro, particularly in SW480 and SW620 cell lines, by decreasing key phosphorylation sites associated with cancer progression.

In vivo studies showed that Y15 not only reduced tumor growth by 28% but also enhanced the effectiveness of chemotherapy agents like 5-FU and oxaliplatin, leading to a 48% greater reduction in tumor size when used in combination, indicating its potential as a therapeutic option for colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy. Heffler, M., Golubovskaya, VM., Dunn, KM., et al.[2022]

BI 853520, a novel small chemical inhibitor of focal adhesion kinase (FAK), significantly reduces primary tumor growth in preclinical mouse models of breast cancer by inhibiting cell proliferation.

While BI 853520 shows strong anti-proliferative effects, its impact on different stages of cancer metastasis varies, suggesting it may be particularly effective for targeting primary tumors rather than metastatic processes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FAK inhibitor BI 853520 exerts anti-tumor effects in breast cancer. Tiede, S., Meyer-Schaller, N., Kalathur, RKR., et al.[2020]

Famitinib, a novel oral multitargeting tyrosine kinase inhibitor, was found to be generally well tolerated in a study of 54 patients with advanced solid cancers, with manageable side effects such as hypertension and mild to moderate bone marrow suppression.

The drug demonstrated a wide range of antitumor activities, achieving eight partial responses and stable disease in 14 patients, particularly in renal cell carcinoma and gastrointestinal stromal tumors, suggesting its potential for further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. Zhou, A., Zhang, W., Chang, C., et al.[2019]

References

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

Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. [2021]

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

Abemaciclib: The First FDA-Approved CDK4/6 Inhibitor for the Adjuvant Treatment of HR+ HER2- Early Breast Cancer. [2022]

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

Selective CDK4/6 Inhibitors: Biologic Outcomes, Determinants of Sensitivity, Mechanisms of Resistance, Combinatorial Approaches, and Pharmacodynamic Biomarkers. [2021]

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

Quality of life with palbociclib plus fulvestrant versus placebo plus fulvestrant in postmenopausal women with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer: patient-reported outcomes from the FLIPPER trial. [2023]

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

Dinaciclib for the treatment of breast cancer. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer-A Systematic Review of Randomized Phase II and III Clinical Trials. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Meta-analysis of selected toxicity endpoints of CDK4/6 inhibitors: Palbociclib and ribociclib. [2022]

9. India pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. [2020]

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

Adverse Cardiovascular Events Associated With Cyclin-Dependent Kinase 4/6 Inhibitors in Patients With Metastatic Breast Cancer. [2023]

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

Overexpression of ErbB2 blocks Taxol-induced apoptosis by upregulation of p21Cip1, which inhibits p34Cdc2 kinase. [2022]

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

Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. [2022]

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

Focal adhesion kinase autophosphorylation inhibition decreases colon cancer cell growth and enhances the efficacy of chemotherapy. [2022]

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

The FAK inhibitor BI 853520 exerts anti-tumor effects in breast cancer. [2020]

15. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of the safety, pharmacokinetics and antitumor activity of famitinib. [2019]