Fadraciclib for Cancer

Recruiting at 4 trial locations

Overseen By Julius Huang, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Cyclacel Pharmaceuticals, Inc.

Must not be taking: Chemotherapy, Immunotherapy, others

Disqualifiers: Brain metastases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

330 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a drug called fadraciclib for individuals with advanced solid tumors or lymphoma who haven't succeeded with standard treatments. The main goal is to assess the safety and effectiveness of fadraciclib, with doses administered in cycles. Individuals who have tried other cancer treatments without success might find this trial suitable, provided they can take pills orally and don't have significant gut issues. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

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.

Is there any evidence suggesting that fadraciclib is likely to be safe for humans?

Research has shown that fadraciclib is generally well-tolerated. In one study, patients with advanced solid tumors took fadraciclib, and researchers found it to be safe, with indications that it might help treat these tumors. Another study demonstrated that fadraciclib was well-tolerated at various doses, with no severe unexpected side effects reported, suggesting its potential safety for humans.

This treatment remains under investigation, so complete safety information is not yet available. However, early results suggest that fadraciclib shows promise in terms of safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Fadraciclib is unique because it targets cyclin-dependent kinases (CDKs), which are crucial for cancer cell growth and survival. This mechanism of action sets it apart from traditional chemotherapy and targeted therapies that often focus on different cellular pathways. By inhibiting CDKs, Fadraciclib aims to disrupt the cancer cell cycle more precisely, potentially reducing side effects and improving effectiveness. Researchers are excited about its oral administration, which offers a more convenient alternative to intravenous treatments, and the potential for optimizing dosage to enhance patient outcomes.

What evidence suggests that fadraciclib might be an effective treatment for cancer?

Research shows that fadraciclib may help treat advanced solid tumors. Earlier studies found it safe and effective, particularly in tumors with certain genetic changes. Fadraciclib targets specific proteins that promote cancer cell growth, causing the cells to stop dividing and die. Early trials indicated that patients with some advanced cancers experienced benefits. While more research is needed, these initial results offer hope for those with limited treatment options. Participants in this trial will receive fadraciclib in escalating doses to determine the optimal phase 2 dose and schedule. ^{1 2 3 6 7}

Who Is on the Research Team?

Mark H Kirschbaum, MD

Principal Investigator

Cyclacel Pharmaceuticals, Inc.

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Fadraciclib

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Dinaciclib, a CDK 1/2/5/9 inhibitor, has shown promising results in preclinical studies and a good safety profile in Phase I trials, making it a potential treatment option for breast cancer and other malignancies.

The review emphasizes the need for a deeper understanding of how CDKs contribute to cancer and suggests that identifying biomarkers for dinaciclib's effectiveness could improve patient selection for clinical trials and enhance treatment strategies, including combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dinaciclib for the treatment of breast cancer. Criscitiello, C., Viale, G., Esposito, A., et al.[2021]

CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, have significantly improved treatment outcomes for hormone receptor-positive and HER2-negative breast cancer, establishing themselves as key options in both first- and second-line therapies.

While these inhibitors effectively prolong overall survival and progression-free survival in patients, they are also associated with notable adverse events, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

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. Stanciu, IM., Parosanu, AI., Nitipir, C.[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]

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]

A total of 1611 individual case safety reports were analyzed, revealing that palbociclib and ribociclib were associated with serious adverse drug reactions (ADRs) like leukopenia and thrombocytopenia, although most patients recovered from these conditions.

In contrast, abemaciclib was linked to mostly non-serious ADRs, indicating a potentially better safety profile, especially when combined with treatments like fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematological Events Potentially Associated with CDK4/6 Inhibitors: An Analysis from the European Spontaneous Adverse Event Reporting System. Martins, V., Jesus, M., Pereira, L., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3596

Efficacy of fadraciclib (CYC065), a novel dual CDK2/9 ... We showed that fadraciclib (CYC065) induces G2/M cell cycle arrest, resulting in anaphase catastrophe as evident by the presence of multipolar ...

2. onclive.com onclive.com/view/fadraciclib-demonstrates-safety-early-efficacy-signals-in-cdkn2a-b-advanced-solid-tumors

Fadraciclib Demonstrates Safety, Early Efficacy Signals in ... Fadraciclib was safe and showed signs of efficacy in advanced solid tumors harboring CDKN2A/B alterations.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04983810

A Study to Investigate Fadraciclib (CYC065), in Subjects ... This is a 2-part, phase 1/2, open-label, multicenter study designed to evaluate the safety, tolerability, PK, pharmacodynamics, PGx, and efficacy of ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9162916/

Cyclin-dependent kinase inhibitor fadraciclib (CYC065) ... A phase 1 trial of fadraciclib in patients with advanced solid tumors (NCT02552953) demonstrated signs of clinical benefit with tolerable ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3125

A phase 1 study evaluating the safety, pharmacokinetics ... Conclusions: Based on data from the CYC065-101 study, fadraciclib appears well tolerated from DL1 to 5. The MTD for the bid dosing schedule is ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7347136/

Fadraciclib (CYC065), a novel CDK inhibitor, targets key ... Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination ...

7. investor.cyclacel.com investor.cyclacel.com/news-releases/news-release-details/cyclacel-presents-phase-1-clinical-data-showing-safety-anti

News Release Preclinical data suggest that fadraciclib may benefit patients with adult and pediatric hematological malignancies such as CLL, AML, ALL, B-cell ...