Z0011001-A PHASE 1/2, OPEN-LABEL, MULTI-CENTER STUDY OF ZN-c3 ADMINISTERED IN COMBINATION WITH ENCORAFENIB AND CETUXIMAB IN ADULTS WITH METASTATIC COLORECTAL CANCER
- Trial ID
- 2022-502267-37-00
- Protocol
- Z0011001 (ZN-c3-016)
- Sponsor
- K-Group Beta Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **RP2D** (recommended phase 2 dose) of **ZN-c3** when administered in combination with **encorafenib** and **cetuximab** in adults with metastatic colorectal cancer. This includes the identification of the **MTD** (maximum tolerated dose), which is crucial for optimizing therapeutic efficacy while minimizing adverse effects in this patient population.
Secondary objectives include:
- Escalation: Assessing the overall safety and tolerability of ZN-c3 in combination with E+C.
- Escalation: Estimating the efficacy of ZN-c3 in combination with E+C.
- Escalation: Evaluating the plasma **PK** of ZN-c3 and its potential metabolites when combined with E+C.
- Escalation: Evaluating the plasma PK of encorafenib when combined with ZN-c3 and cetuximab.
- Expansion: Assessing the efficacy of ZN-c3 in combination with E+C.
- Expansion: Assessing the overall safety and tolerability of ZN-c3 in combination with E+C.
- Expansion: Evaluating the plasma PK of ZN-c3 and its potential metabolites at steady state when combined with E+C.
- Expansion: Evaluating the plasma PK of encorafenib at steady state when combined with ZN-c3 and cetuximab.
- Expansion: Evaluating the effect of encorafenib on the plasma PK of ZN-c3 at steady state.
- Expansion: Confirming the mutational status of tumor tissue or plasma **ctDNA**.
Participants
The clinical trial involves a total of **32 participants** diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects who are at least 18 years of age, ensuring they are legally recognized as adults. Participants were selected based on their ability to provide informed consent and their willingness to comply with the study's requirements, including scheduled visits and lifestyle considerations. The trial includes individuals with adequate bone marrow, hepatic, and renal function, as well as those with a body weight of at least 40 kg. Participants must have histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma with a documented BRAF V600E mutation. The presence of measurable disease per RECIST version 1.1 guidelines is required, along with the availability of adequate tumor tissue for retrospective analysis. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating a relatively stable general health status. The study does not exclude vulnerable populations, allowing for a diverse representation of individuals affected by this condition.
Plans and Procedures
The clinical trial is designed as a **Phase 1/2, open-label, multi-center study** to evaluate the combination of **ZN-c3**, **encorafenib**, and **cetuximab** in adult participants with **metastatic colorectal cancer**. The primary objective is to determine the recommended phase 2 dose (RP2D) of ZN-c3 when administered with encorafenib and cetuximab, including the identification of the maximum tolerated dose (MTD). The trial will assess the incidence of dose-limiting toxicities (DLTs) during dose escalation and the overall response rate (ORR) in the expansion cohort. Secondary endpoints include the incidence and severity of adverse events (AEs), pharmacokinetic parameters, and the BRAF V600E mutational status.
The trial is expected to commence recruitment on July 6, 2023, and conclude by December 31, 2026. Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, adequate bone marrow, hepatic, and renal function, and documented evidence of a BRAF V600E mutation. The study will include regular follow-up visits to monitor safety, efficacy, and pharmacokinetics, with the end-of-study visit marking the completion of the participant's involvement. The expected duration of participation will vary depending on individual response and tolerance to the treatment regimen.
Participants may be withdrawn from the study early due to reasons such as the occurrence of unacceptable toxicity, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that all procedures are conducted in accordance with regulatory requirements and best practices in clinical research.
Treatment
The clinical trial involves the administration of **Encorafenib**, a **BRAF V600-mutant kinase inhibitor**. Encorafenib is provided in the form of a hard capsule and is administered orally. The specific dosage and frequency of administration are determined based on the study protocol, with the aim of identifying the recommended phase 2 dose (RP2D) and the maximum tolerated dose (MTD) when combined with other treatments. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.
**Cetuximab** is another treatment used in this study, provided as a solution for infusion. It is administered via intravenous infusion. Cetuximab is used in combination with Encorafenib to evaluate its efficacy in treating adults with metastatic colorectal cancer. The administration schedule is designed to optimize therapeutic outcomes while monitoring for any adverse effects.
The experimental medication **Azenosertib**, also known as ZN-c3 or KP-2638, is a small-molecule inhibitor of **WEE1 tyrosine kinase**. It is provided in the form of a film-coated tablet and administered orally. The trial aims to determine the optimal dosing regimen for Azenosertib when used in combination with Encorafenib and Cetuximab. The study protocol includes detailed instructions for dosing and monitoring participant compliance to ensure accurate assessment of the drug's safety and efficacy.
No placebo or standard-of-care therapy is used as a comparator in this trial. The focus is on evaluating the combination of Encorafenib, Cetuximab, and Azenosertib in the specified patient population. The trial is conducted in accordance with regulatory guidelines to ensure the safety and well-being of participants.
Efficacy
The efficacy of the clinical trial involving the combination of **ZN-c3**, **encorafenib**, and **cetuximab** in adults with metastatic colorectal cancer will be assessed through several primary and secondary endpoints. The primary endpoints include the incidence of dose-limiting toxicities (DLTs) during the dose escalation phase and the objective response rate (ORR) by Investigator assessment in the expansion cohort. The ORR is defined as the proportion of participants achieving a confirmed best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST version 1.1 guidelines.
Secondary endpoints will evaluate additional efficacy parameters such as the duration of response (DOR), progression-free survival (PFS), disease control rate (DCR), and time to response (TTR) by Investigator assessment. The trial will also monitor the incidence and severity of adverse events (AEs) graded according to the NCI CTCAE v5.0, as well as changes in clinical laboratory parameters, vital signs, and electrocardiograms (ECGs). Pharmacokinetic (PK) parameters of **ZN-c3** and **encorafenib**, including Cmax, Tmax, and AUC, will be measured to further assess the treatment's efficacy and safety profile.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female participants minimum legal adult age or ≥18 years (whichever is greater) at the time of informed consent.
- Body weight ≥ 40 kg.
- Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
- Histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma.
- Documented evidence of a BRAF V600E mutation in tumor tissue or blood (ie, ctDNA) as previously determined by PCR or NGS-based laboratory assay, or a CE-marked assay for Europe, in a CLIA or similarly certified laboratory. (A molecular report clearly documenting the presence of the BRAF V600E mutation (and other molecular findings from sample analysis as performed during the normal course of clinical care) must be provided for confirmation that testing meets eligibility during Screening.)
- Presence of measurable disease per RECIST version 1.1 guidelines, as assessed by investigator and evidenced by available baseline tumor scan.
- Confirmation of availability of adequate tumor tissue (primary or metastatic; archival or newly obtained; block or slides) which may be used for retrospective analysis of BRAF V600E mutation status. Tumor sample can be archival or de novo (newly collected fixed biopsy sample) and must be in an FFPE block or provide a minimum of 15-20 unstained slides of analyzable tissue. Participants with <15 unstained slides may also be considered eligible after consultation with Sponsor or designee. Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E mutation testing. It is recommended that the tissue block be obtained from a biopsy or surgery that was performed within 2 years prior to study enrollment. Please consult the study clinician to determine if samples are older and/or if there are fewer than the required number of slides with analyzable tissue. A newly obtained tumor tissue biopsy must be provided prior to enrollment for participants unable to provide adequate archival tumor tissue, unless there is a safety concern. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible.
- Disease progression after 1 or 2 previous systemic regimens for metastatic disease. Note: Participants with early stage disease (eg, Stages I-III) treated with surgery followed by chemotherapy (eg, treatment in the adjuvant setting) or have received prior systemic neoadjuvant therapy with or without radiation who present with new lesions or evidence of disease recurrence during or within 6 months of the last dose of chemotherapy would be considered as having received 1 prior systemic therapy in the metastatic setting.
- ECOG PS of 0 or 1.
- Adequate bone marrow function characterized by the following at screening: a. ANC ≥1.5 × 109/L (excluding measurements obtained within 7 days after daily administration of filgrastim/sargramostim or within 3 weeks after administration of pegfilgrastim, as applicable). b. Platelets ≥100 × 109/L(excluding measurements obtained within 3 days after transfusion of platelets). c. Hemoglobin ≥9.0 g/dL (excluding measurements obtained within 2 weeks after blood transfusion).
- Adequate hepatic and renal function characterized by the following at screening: a. Serum Total bili ≤ 1.5 x upper limit of normal ULN and 2 mg/dL. Note: Total bili > 1.5 x ULN is allowed if direct (conjugated) ≤ 1.5 x ULN and indirect (unconjugated) bilirubin is ≤ 4.25 x ULN. Note: Participants with hyperbilirubinemia due to non-hepatic cause (eg, hemolysis, hematoma) may be enrolled following discussion and agreement with the medical monitor. b. AST and ALT ≤ 2.5 x ULN, or ≤ 5.0 × ULN in the presence of liver metastases. c. Adequate renal function defined by an estimated creatinine clearance ≥50 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standard method. d. Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits. Note: Replacement treatment to achieve adequate electrolytes will be allowed.
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.
Exclusion Criteria
- Documented clinical disease progression (eg, worsening of performance status, clinical symptoms, or clinically significant laboratory parameters demonstrating worsening of disease) or radiographic disease progression during the screening period.
- Leptomeningeal disease.
- Symptomatic brain metastasis. Note: Participants previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for ≥4 weeks prior to enrollment.
- Presence of acute or chronic pancreatitis.
- History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to enrollment.
- Unable to swallow, retain, and absorb oral medications.
- Impaired gastrointestinal function (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection) or disease or any other abnormality which may significantly alter the absorption of oral study intervention (e.g. active peptic ulcer, requirement for IV alimentation) or recent changes in bowel function suggesting current or impending bowel obstruction.
- Clinically significant cardiovascular diseases, including any of the following: a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to enrollment. b. Congestive heart failure requiring treatment (New York Heart Association Class ≥II). c. Recent history (within 1 year prior to randomization) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia). d. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to enrollment. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (eg, massive or sub-massive) deep vein thrombosis or pulmonary emboli. Note: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks. Note: Participants with thromboembolic events related to indwelling catheters (including PICC lines) or other procedures may be enrolled
- Triplicate average QTcF interval ≥470 ms based on the Screening ECG, or a history of prolonged QT syndrome. Note: Participants with BBB or with an implanted cardiac pacemaker may enroll into the study upon agreement between the investigator and Sponsor or designee.
- History or current evidence of congenital or known family history of LQTS or TdP.
- Evidence of active noninfectious pneumonitis.
- Evidence of active and uncontrolled bacterial or viral infection within 2 weeks prior to start of any of the study interventions, with certain exceptions, as noted below, for chronic infection with HIV, HBV or HCV. Participants with an infection receiving treatment (antibiotic, antifungal, or antiviral treatment) must have completed such treatment and the infection must be considered controlled/resolved by the investigator at least 2 weeks before start of any of the study interventions. Note: For COVID-19/SARS-CoV-2, SARS-CoV-2 testing is not mandated for study entry, and testing should follow local clinical practice standards. Any participant with a positive test result for SARS-CoV-2 infection during screening, is known to have asymptomatic infection or is suspected of having SARS-CoV-2, is excluded. Once the infection resolves, the participant may be considered for re-screening.
- Participants with known positivity for HIV (testing is not required unless mandated locally) are ineligible unless they meet all of the following: a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated; b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections; c. A CD4 count >250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests
- Active hepatitis B or hepatitis C infection (testing not required unless mandated locally) a. Active HBV is defined as any of the following: • HBsAg(+), HBV DNA >200 IU/mL. • HBsAg(+), HBV DNA ≤200 IU/mL and persistent or intermittent elevation of ALT/AST (eg, above normal range) and/or liver biopsy showing chronic hepatitis with moderate or severe necroinflammation. Note: Participants who are HBsAg(-), HBcAb(+) are eligible and should be monitored/treated as per local standard of care. b. Active HCV is defined as: • HCV antibody positive; AND • Presence of HCV RNA.
- Concurrent or previous other malignancy within 2 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen’s disease or prostate cancer with a Gleason score ≤6. Participants with a history of other curatively treated malignancies with low risk of recurrence not listed may also be considered eligible after consultation with Sponsor or designee.
- Residual NCI CTCAE v5.0 ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
- Other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or administration of any of the study interventions or, in the investigator’s judgment, make the participant inappropriate for the study.
- Dose Escalation part: Prior therapy with any WEE1 inhibitor. Dose Expansion part: Prior therapy with any WEE1 inhibitor or any selective BRAFi inhibitor (eg, encorafenib, dabrafenib, vemurafenib, XL281/BMS-908662) or any EGFR inhibitor (eg, cetuximab, panitumumab).
- Any chemotherapy (or for dose escalation part only, BRAFi or EGFR inhibitor, as applicable) within 21 days or 5 half-lives (whichever is longer) prior to start of study treatment.
- Use of prescription or non-prescription drugs, or consumption of food and herbal supplements of the following: a. strong or moderate CYP3A inhibitors, for 5 half-lives plus 14 days prior to the start of the first treatment; b. strong or moderate CYP3A inducers, for 5 half-lives plus 14 days prior to the start of the first treatment; c. P‑gp inhibitors, for 5 half-lives prior to the start of the first treatment;
- Major surgery or completion of radiation therapy ≤4 weeks prior to enrollment or radiation therapy that included >30% of the bone marrow.
- Previous administration with an investigational drug (including investigational medicinal products, devices, and investigational vaccines) ≤30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of any of the study interventions (whichever is longer).
- Has had an allogeneic tissue/solid organ transplant.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 06 Jul 2023 | 10 |
 Hungary | Not Recruiting | 06 Jul 2023 | 10 |
 Italy | Not Recruiting | 06 Jul 2023 | 10 |
 Poland | Not Recruiting | 06 Jul 2023 | 10 |
 Spain | Not Recruiting | 06 Jul 2023 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Azenosertibalso known as ZN-c3; KP-2638 | Test | FILM-COATED TABLET | ORAL USE | — | — | PRD9495923 |
ENCORAFENIB | Test | — | ORAL USE | — | — | SUB177218 |
CETUXIMAB | Test | — | INTRAVENOUS INFUSION | — | — | SUB01178MIG |
Azenosertibalso known as ZN-c3; KP-2638 | Test | FILM-COATED TABLET | ORAL USE | — | — | PRD9495924 |