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CYC140 will be administered as a single agent on Day 1 and Day 8 of each 3 week cycle

CYC140

Mark Kirschbaum, MD

Hind Alazzawi

Gautam Borthakur, MD

A Phase I Pharmacologic Study of CYC140, a polo-like kinase 1 inhibitor, in Patients with Advanced Leukemias or Myelodysplastic Syndromes

This is a First in Human, open-label, single arm, dose escalation study in patients with advanced leukemias or myelodysplastic syndromes. Patients will receive CYC140 as a 1 hr infusion once a week for 2 weeks followed by 1 week of rest on an outpatient basis. One treatment cycle is 3 weeks.

One to three patients will be entered at a given dose level of CYC140. During the first cycle, all patients will be evaluated for DLTs. If DLT occurs, additional patients (up to 3) will be dosed at that dose. If no additional DLTs observed, dose escalation will continue per protocol. If a DLT does occur, dose escalation will be stopped. At least 6 patients will be treated at the RD to confirm its tolerability.

A Phase I Study of CYC140, a PLK-1 Inhibitor, in Advanced Leukemias or MDS

A Phase I Pharmacologic Study of CYC140, a Polo-like Kinase 1 Inhibitor, in Patients With Advanced Leukemias or Myelodysplastic Syndromes

plasma drug exposure area under the curve (AUC)

M.D. Anderson Cancer Center

Cyclacel Pharmaceuticals, Inc.

Immune System Diseases

Leukemia, Lymphoid

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

All Drugs and Chemicals

Ibrutinib

LLC patients with prior treatment with BTKi - Underlying tenet: these patients have been treated with a BTKi in at least one of two or more prior lines of therapy and progressed - FULL POPULATION

LLC Patients who progressed BTKi and failed VEN (defined as patients who discontinued VEN due to disease progression, intolerability, or failure to achieve an objective response within 3 months of initiating therapy; small patient population) - Tenet: these patients have been treated with both BTKi and VEN in any one of the prior two lines of therapy and progressed

Loïc YSEBAERT

Data evaluating and quantifying real-world outcomes of patients post-ibrutinib discontinuation, as well as outcomes of patients who have progressed on a Bruton tyrosine kinases inhibitors (BTKi) and received prior venetoclax are very limited. There are no robust studies specifically designed to assess outcomes of patients with chronic lymphocytic leukemia (CLL) receiving third line or subsequent treatments. As such, there is no established standard of care for these multiple Relapsed/Refractory (RR) patients. Furthermore, despite new oral agents approved in third-line RR CLL, there are limited published data on how to best sequence these agents and how to manage patients who fail these therapies. As the best salvage therapy in patients who fail all available oral these agents is unknown, this is a population of patients with unmet medical need.

The aim of this study is to determine unmet need and treatment patterns of data from two types of populations, all previously exposed to ibrutinib (or other BTKi) for the full patient population and both ibrutinib (or other BTKi and venetoclax) for the narrow patient population, where these agents failed these subcategories of patient populations, at least in 3rd line therapy (in other words, having at least received two lines of therapy before)

* Patients with prior treatment with BTKi (full patient population) - Underlying tenet: these patients have been treated with a BTKi in at least one of two or more prior lines of therapy and progressed - FULL POPULATION
* Patients who progressed BTKi and failed VEN (defined as patients who discontinued venetoclax (VEN) due to disease progression, intolerability, or failure to achieve an objective response within 3 months of initiating therapy; small patient population) - Tenet: these patients have been treated with both BTKi and VEN in any one of the prior two lines of therapy and progressed. - NARROW POPULATION

REfractorinesS to Ibrutinib BTKi and Systemic Targeted Therapy

Overall response rate (complete, partial, stable) for each treatment received

Bristol-Myers Squibb

French Innovative Leukemia Organisation

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Leukemia, Lymphocytic, Chronic, B-Cell

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

Lipid Regulating Agents

Venetoclax

Azacitidine

Decitabine

Pitavastatin

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Enzyme Inhibitors

Patients receive Pitavastatin (PIT) 1 mg PO daily. For CLL patients, they will also receive stabilized Venetoclax (VEN) 400mg PO daily. For AML patients, they will VEN mg PO daily when dosing in combination with azacitidine or decitabine.

The 1 mg/day dose level will be held in reserve to allow dose reduction in those patients who cannot tolerate DL1.

Patients receive Pitavastatin (PIT) 2 mg PO daily. For CLL patients, they will also receive stabilized Venetoclax (VEN) 400mg PO daily. For AML patients, they will VEN mg PO daily when dosing in combination with azacitidine or decitabine.

This is the starting dose level for the study.

Patients receive Pitavastatin (PIT) 4 mg PO daily. For CLL patients, they will also receive stabilized Venetoclax (VEN) 400mg PO daily. For AML patients, they will VEN mg PO daily when dosing in combination with azacitidine or decitabine.

If DL1 is well tolerated, the next cohort will progress to this dose level.

Elizabeth Brem, MD

This is a phase I, dose-escalation, open-label clinical trial determining the safety and tolerability of adding Pitavastatin to Venetoclax in subjects with chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). These are subjects who are newly diagnosed subjects with AML who are ineligible for intensive induction chemotherapy, relapsed/refractory CLL or newly diagnosed CLL.

Pitavastatin in Combination With Venetoclax for Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia

A Phase 1 Open-Label, Dose Escalation Study of Pitavastatin in Combination With Venetoclax in Patients With Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia

Change in PK parameters from baseline to Cycle 1 to determine if concomitant administration of PIT affects concentrations of VEN when given in combination with PIT.

BH3 profiling on pretreatment and post-treatment bloods samples to assess whether add on treatment with PIT increases apoptotic priming. In dynamic BH3 profiling, the degree of mitochondrial outer membrane permeabilization (MOMP) after exposure to drug is compared to the untreated baseline to quantify the change in priming or induced by exposure to a drug.

Determination of the maximum tolerated dose (MTD) will be utilized to evaluate the safety and tolerability of adding to PIT to treatment with stable doses of VEN ± anti-CD20 antibodies (patients with CLL) or VEN with hypomethylating agents (patients with AML).

Determination of the recommended Phase 2 dose (RP2D) will be utilized to evaluate the safety and tolerability of adding to PIT to treatment with stable doses of VEN ± anti-CD20 antibodies (patients with CLL) or VEN with hypomethylating agents (patients with AML).

To evaluate the safety and tolerability of administering PIT in combination with VEN-containing SOC in patients with AML or CLL .

To evaluate the adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0.

Primary efficacy endpoint is the complete response rate of subjects who receive PIT when given with VEN-containing SOC regimens. The 2018 International Working Group for Chronic Lymphocytic Leukemia (iwCLL) and 2017 European LeukemiaNet (ELN) definitions of Complete Response (CR) will be utilized to determine the CR rate.

Secondary efficacy endpoints are the rates for the other response categories of subjects who receive PIT when given with VEN-containing SOC regimens. The 2018 International Working Group for Chronic Lymphocytic Leukemia (iwCLL) and 2017 European LeukemiaNet (ELN) definitions of Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) will be utilized to determine the rates for each of these categories.

Responders are defined as individuals who either received a CR or PR. Responders = CR+PR.

Changes in safety status, such as Eastern Cooperative Oncology Group (ECOG), performance status, vital signs and laboratory assessments throughout treatment through the trial.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Study of CYC140, a PLK-1 Inhibitor, in Advanced Leukemias or MDS	NCT03884829	AML, Adult Myelodysplastic... ALL, Adult CML, Refractory CLL, Refractory	CYC140	18 Years -	Cyclacel Pharmaceuticals, Inc.
A Phase I Study of CYC140, a PLK-1 Inhibitor, in Advanced Leukemias or MDS	NCT03884829	AML, Adult Myelodysplastic... ALL, Adult CML, Refractory CLL, Refractory	CYC140	18 Years -	Cyclacel Pharmaceuticals, Inc.
REfractorinesS to Ibrutinib BTKi and Systemic Targeted Therapy	NCT05621148	CLL, Relapsed CLL, Refractory Bruton Tyrosine... Small Lymphocyt...		18 Years -	French Innovative Leukemia Organisation
Pitavastatin in Combination With Venetoclax for Chronic Lymphocytic Leukemia or Acute Myeloid Leukemia	NCT04512105	Acute Myeloid L... Chronic Lymphoc... AML, Adult CLL CLL, Relapsed CLL, Refractory	Pitavastatin Venetoclax	18 Years -	University of California, Irvine

Spots Global Cancer Trial Database for cll, refractory