A Study of ZN-c3 in Patients With Platinum-Resistant Ovarian Cancer

Solid Tumor Clinical Trial

Official title:

A Phase 1b Study of ZN-c3 in Combination With Chemotherapy in Patients With Platinum-Resistant Ovarian, Peritoneal or Fallopian Tube Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04516447
• Other study ID #: ZN-c3-002
• Status: Recruiting
• Phase: Phase 1
• Start date: October 26, 2020
• Est. completion date: August 31, 2024

Study information

• Verified date: September 2023
• Source: K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc
• Contact: K-Group, Beta, Inc., a subsidiary of Zentalis Pharmaceuticals
• Phone: 8582634333
• Email: medicalaffairs[@]zentalis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1b open-label, multicenter study, evaluating the safety, tolerability, preliminary clinical activity, pharmacokinetics (PK), and pharmacodynamics of ZN-c3 in combination with other drugs.

Description:

This is a Phase 1b open-label, multicenter study, evaluating the safety, tolerability, preliminary clinical activity, pharmacokinetics (PK), and pharmacodynamics of ZN-c3. This study consists of 4 cohorts in participants with platinum-resistant ovarian, peritoneal, or fallopian tube cancer. Each cohort will test a combination of ZN-c3 with either pegylated liposomal doxorubicin (PLD), carboplatin, paclitaxel, or gemcitabine.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: August 31, 2024
• Est. primary completion date: January 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Provision of written informed consent prior to initiation of any study-related procedures that are not considered standard of care.
• Females = 18 years of age or the minimum legal adult age (whichever is greater) at the time of informed consent.
• ECOG performance status = 2.
• Histologically or cytologically confirmed high-grade serous epithelial ovarian carcinoma, fallopian tube, or peritoneal carcinoma.
• Subjects must have received 1 or 2 prior therapeutic regimens/lines of therapy in the advanced or metastatic setting.
• The disease must be platinum-resistant, i.e., the Platinum-Free Interval (PFI) must have been < 6 months. Platinum refractory disease, i.e., PD during first-line platinum-based therapy is allowed.
• Measurable disease per RECIST version 1.1.
• Adequate hematologic and organ function as defined by the following criteria:

1. ANC = 1.5 × 10^9/L; excluding measurements obtained within 7 days after daily administration of filgrastim/sargramostim or within 3 weeks after administration of pegfilgrastim.

2. Platelet count = 100 × 10^9/L; excluding measurements obtained within 3 days after transfusion of platelets or within 3 weeks after administration of platelet growth factors.

3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =3 × upper limit of normal (ULN). If liver function abnormalities are due to underlying liver metastases, AST and ALT = 5 x ULN.

4. Total serum bilirubin = 1.5 × ULN or = 3 × ULN in the case of Gilbert's disease.

5. Serum creatinine = 1.5 x ULN or creatinine clearance (CrCl) = 60 mL/min.

• Female subjects of childbearing potential must have a negative serum beta human chorionic gonadotropin (ß-hCG) test and agree to use an effective method of contraception per institutional standard.
• Left ventricular ejection fraction (LVEF) = 50% or within normal limits of the institution (only for subjects treated with PLD).

Exclusion Criteria:

• Histology of abdominal adenocarcinoma of unknown origin or diagnosis of a borderline ovarian tumor.
• Any of the following treatment interventions within the specified time frame prior to

Cycle 1 Day 1:

1. Major surgery within 28 days.

2. Radiation therapy within 21 days.

3. Autologous or allogeneic stem cell transplant within 3 months.

4. Inability to discontinue treatment for 5 half-lives or 14 days (whichever is longer) prior to Cycle 1 Day 1 with prescription or non-prescription drugs, or to

discontinue consumption of food and herbal supplements, that are:

• strong and moderate CYP3A inhibitors
• strong and moderate CYP3A inducers
• P-gp inhibitors
• A serious illness or medical condition(s) including, but not limited to, the

following:

1. Brain metastases that require immediate treatment or are clinically or radiographically unstable.

2. Leptomeningeal disease that requires or is anticipated to require immediate treatment.

3. Myocardial impairment of any cause.

4. Significant gastrointestinal abnormalities.

5. Active or uncontrolled infection.

6. Any evidence of small bowel obstruction as determined by air/fluid levels on computed tomography (CT) scan, recent hospitalization for small bowel obstruction within 3 months prior to Cycle 1 Day 1, or recurrent paracentesis or thoracentesis within 6 weeks prior to Cycle 1 Day 1.

• Unresolved toxicity of Grade > 1 attributed to any prior therapies (excluding Grade 2 neuropathy, alopecia or skin pigmentation).
• Pregnant or lactating females (including the cessation of lactation) or females of childbearing potential who have a positive serum pregnancy test within 14 days prior to Cycle 1 Day 1.
• Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy.
• 12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of > 480 msec, except for subjects with atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that render the QT measurement invalid.
• History or current evidence of congenital long QT syndrome.

Related Conditions & MeSH terms

• Carcinoma, Ovarian Epithelial
• Epithelial Ovarian Cancer
• Fallopian Tube Cancer
• Fallopian Tube Neoplasms
• Ovarian Neoplasms
• Peritoneal Cancer
• Solid Tumor

Intervention

Drug:
• ZN-c3
Investigational drug
• Carboplatin
Carboplatin is an approved drug
• Pegylated liposomal doxorubicin
Pegylated liposomal doxorubicin (PLD) is an approved drug
• Paclitaxel
Paclitaxel is an approved drug
• Gemcitabine
Gemcitabine is an approved drug

Locations

Country	Name	City	State
Australia	Site 2706	Melbourne	Victoria
Australia	Site 2705	Nedlands	Western Australia
Australia	Site 2707	South Brisbane	Queensland
Australia	Site 2708	Sunshine Coast	Queensland
Bosnia and Herzegovina	Site 1001	Banja Luka
Bosnia and Herzegovina	Site 1002	Sarajevo
Bosnia and Herzegovina	Site 1003	Tuzla
Bulgaria	Site 1202	Panagyurishte
Bulgaria	Site 1201	Sofia
Georgia	Site 1401	Tbilisi
Korea, Republic of	Site 2901	Busan
Korea, Republic of	Site 2903	Seoul
Korea, Republic of	Site 2904	Seoul
Serbia	Site 1902	Belgrade
United States	Site 0264	Aurora	Colorado
United States	Site 0104	Boston	Massachusetts
United States	Site 0259	Durham	North Carolina
United States	Site 0103	Houston	Texas
United States	Site 0196	Nashville	Tennessee
United States	Site 0173	New York	New York
United States	Site 0191	Providence	Rhode Island
United States	Site 0111	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
K-Group, Beta, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc

Countries where clinical trial is conducted

United States,  Australia,  Bosnia and Herzegovina,  Bulgaria,  Georgia,  Korea, Republic of,  Serbia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To investigate the pharmacodynamics of ZN-c3 on the biological activity of ?H2AX	Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of ?H2AX	Through completion, approximately 40 months
Other	To investigate the pharmacodynamics of ZN-c3 on the biological activity of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1)	Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of phosphorylated cyclin-dependent kinase 1 (phospho-CDK1)	Through completion, approximately 40 months
Other	To investigate the pharmacodynamics of ZN-c3 on the biological activity of Ki-67	Biological activity in pre- versus post-dose tumor tissue and hair follicle samples of Ki-67	Through completion, approximately 40 months
Other	To investigate the pharmacodynamics of ZN-c3 on Baseline Cyclin E expression	Including, but not limited to, Baseline Cyclin E expression in pre-dose tumor tissue	Through completion, approximately 40 months
Other	To investigate the pharmacodynamics of ZN-c3 on molecular determinants of sensitivity to ZN-c3	Molecular determinants of sensitivity to ZN-c3 including but not limited to Baseline DNA Damage Repair (DDR) gene mutations, deletions, copy number variations or indices of genetic instability in either tumor tissue or cell-free DNA (cfDNA)	Through completion, approximately 40 months
Other	To characterize the PK of ZN-c3 in tumor tissue	ZN-c3 concentrations (and its potential metabolites as applicable) in tumor tissue	At Cycle 1 Day 1 and Cycle 2 Day 1 (pre-dose) (each cycle is 28 days for PLD or paclitaxel, and 21 days for carboplatin or gemcitabine)
Primary	To investigate the safety and tolerability of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Incidence and severity of adverse events (AEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0	Through completion, approximately 40 months
Primary	To identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Incidence and severity of dose-limiting toxicities (DLTs) in DLT-evaluable subjects during Cycle 1	Through Cycle 1 (cycle is 28 days for PLD or paclitaxel, and 21 days for carboplatin or gemcitabine)
Secondary	To obtain estimates of clinical activity by determining the objective response rate (ORR) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Objective response rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors RECIST version 1.1	Through completion, approximately 40 months
Secondary	To obtain estimates of clinical activity by determining the duration of response (DOR) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Duration of response (DOR) as defined by Response Evaluation Criteria in Solid Tumors RECIST version 1.1	Through completion, approximately 40 months
Secondary	To obtain estimates of clinical activity by determining the progression-free survival (PFS) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Progression-free survival (PFS) as defined by RECIST version 1.1 and clinical criteria	Through completion, approximately 40 months
Secondary	To obtain estimates of clinical activity by determining the time to CA125 progression of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Time to CA125 progression according to the Gynecologic Cancer Intergroup (GCIG) criteria	Through completion, approximately 40 months
Secondary	To investigate the plasma pharmacokinetics (PK) of ZN-c3 in combination with PLD, carboplatin, paclitaxel, or gemcitabine	Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable)	Through completion, approximately 40 months