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Cyclacel Presents Phase 1 Clinical Data Showing Safety, Anti-Tumor Activity and Good Oral Bioavailability of Fadraciclib in Patients With Advanced Solid Tumors at the EORTC-NCI-AACR Symposium 2020
"In addition to good oral bioavailability, we are pleased to report a durable PR with continuing shrinkage of target lesions reaching 92% in a patient with MCL1 amplified endometrial cancer. Four other patients achieved stable disease," said Spiro Rombotis, Chief Executive Officer of
Presentation Highlights: Phase 1 Safety, Pharmacokinetic and Pharmacodynamic Study of Fadraciclib (CYC065), a Cyclin-Dependent Kinase Inhibitor, in Patients with Advanced Cancers
Twenty-four heavily pretreated patients with various advanced solid tumors, including ovarian, endometrial/uterine, breast, and fallopian cancer, were enrolled in part 2 with intravenous (i.v.) administration and five patients in part 3 with oral administration of this ongoing Phase 1, open label, dose escalation study.
- Determine MTD and recommended phase 2 dose (RP2D)
- Evaluate pharmacokinetics
- Assess pharmacodynamic markers
- Administration schedule of flat dosing schedule of single-agent fadraciclib (CYC065) given either by 1-hour infusion or orally on days 1, 2, 8 and 9 every 3 weeks
- The trial advanced through four dose levels (DL) with a range of 90mg to 213mg, administered as a 1-hour intravenous infusion on days 1, 2, 8 and 9 and two DL with a range of 75mg to 150mg as an orally administered formulation on days 1, 2, 8 and 9; both in 3-week cycles.
- Eleven patients were treated at DL4 (213 mg). Dose limiting toxicity at DL4 was reversible neutropenia. The 160mg dose level is being expanded to define RP2D.
- No major or unexpected toxicities were observed.
Efficacy (n=24, i.v. formulation only):
- One confirmed partial response and two stable disease (SD) out of 11 patients on 213mg i.v. formulation:
• PR after a month and a half on fadraciclib: MCL1-amplified endometrial cancer; failed seven lines of prior therapy; continuing treatment for more than 16 months with 92% reduction in target tumor lesions.
• SD: Cyclin E amplified ovarian cancer with 29% tumor shrinkage after four months.
• SD: Fallopian tube adenocarcinoma (undetermined protein level).
- Increases in fadraciclib exposure with increasing dosing levels.
- High oral bioavailability and comparable PK profile after oral or 1 hour-infusion administration.
The presentation was part of the 32nd EORTC-NCI-AACR (ENA) Symposium 2020 and is available on the "Presentation and Events" section of the
Title: Phase 1 safety, pharmacokinetic and pharmacodynamic study of fadraciclib (CYC065), a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953)
Session Title: Late Breaking and Best Proffered Papers
Session Date and Time: Saturday 24 October 15:05 CET
Presentation Number: ORAL-002
About Cyclin-Dependent Kinases and Fadraciclib
Cyclin-dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. Fadraciclib is a potent orally and intravenously available inhibitor of CDK2 and CDK9.
Fadraciclib is in an ongoing Phase 1, first-in-human study in patients with advanced solid tumors. In part 1 of the study, target engagement and durable suppression of the MCL1 biomarker were observed after a single dose of fadraciclib by 4-hour infusion. Tumor shrinkage and stable disease were observed in five patients with cyclin E, MCL1 or MYC amplified advanced cancers treated at the RP2D. In the ongoing part 2 of the study evaluating a more intensive dosing regimen, a heavily pretreated patient with MCL1 amplified endometrial cancer achieved a radiographically confirmed partial response (PR) after a month and a half on fadraciclib. This patient continues on therapy for more than a year and reduction in her target tumor lesions has reached 92%. An additional patient with cyclin E amplified ovarian cancer achieved stable disease with 29% tumor shrinkage. Part 3 is investigating an oral dose formulation.
Fadraciclib is also being evaluated in Phase 1 combination studies with venetoclax in relapsed or refractory CLL and in relapsed or refractory AML or MDS. Similarly to FDA-approved CDK4/6 inhibitors, fadraciclib may be most useful in combination with other anticancer drugs, including BCL2 inhibitors, such as venetoclax, or HER2 inhibitors, such as trastuzumab. Preclinical data suggest that fadraciclib may benefit patients with adult and pediatric hematological malignancies such as CLL, AML, ALL, B-cell lymphomas, multiple myeloma and certain cyclin E-addicted or MYC-amplified solid tumors, including certain forms of breast cancer, neuroblastoma, ovarian cancer and uterine serous carcinoma.
This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and intended utilization of
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