ZN-c3 in Adult Participants With Metastatic Colorectal Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

K-Group Beta Inc.

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

17 Jul 2023 → 25 Nov 2025

Decision date (initial)

2023-06-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

K-Group Beta, Inc.

External identifiers

EU CT number

2022-502267-37-00

WHO UTN

U1111-1287-6564

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Efficacy

To determine the RP2D (recommended phase 2 dose) of ZN-c3 administered in combination with E+C (encorafenib/cetuximab), including identification of the MTD (maximum tolerated dose).

Secondary objectives 10

1. Escalation: To assess the overall safety and tolerability of ZN-c3 administered in combination with E+C.
2. Escalation: To estimate the efficacy of ZN-c3 administered in combination with E+C.
3. Escalation: To evaluate the plasma PK of ZN-c3 (and its potential metabolites as applicable) when given in combination with E+C with E+C.
4. Escalation: To evaluate the plasma PK of encorafenib when given in combination with ZN-c3 and cetuximab.
5. Expansion: To assess the efficacy of ZN-c3 administered in combination with E+C.
6. Expansion: To assess the overall safety and tolerability of ZN-c3 administered in combination with E+C.
7. Expansion: To evaluate the plasma PK of ZN-c3 (and its potential metabolites as applicable) when given in combination with E+Cwith E+C at steady state.
8. Expansion: To evaluate the plasma PK of encorafenib when given in combination with ZN-c3 and cetuximab at steady state.
9. Expansion: To evaluate the effect of encorafenib on plasma PK of ZN-c3 at steady state.
10. Expansion: To confirm mutational status of tumor tissue or plasma ctDNA.

Conditions and MedDRA coding

metastatic colorectal cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male or female participants minimum legal adult age or ≥18 years (whichever is greater) at the time of informed consent.
2. Body weight ≥ 40 kg.
3. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
4. Histologically or cytologically confirmed metastatic Stage IV colorectal adenocarcinoma.
5. 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.)
6. Presence of measurable disease per RECIST version 1.1 guidelines, as assessed by investigator and evidenced by available baseline tumor scan.
7. 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.
8. 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.
9. ECOG PS of 0 or 1.
10. 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).
11. 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.
12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.

Exclusion criteria 23

1. 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.
2. Leptomeningeal disease.
3. 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.
4. Presence of acute or chronic pancreatitis.
5. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to enrollment.
6. Unable to swallow, retain, and absorb oral medications.
7. 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.
8. 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
9. 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.
10. History or current evidence of congenital or known family history of LQTS or TdP.
11. Evidence of active noninfectious pneumonitis.
12. 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.
13. 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
14. 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.
15. 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.
16. Residual NCI CTCAE v5.0 ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
17. 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.
18. 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).
19. 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.
20. 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;
21. Major surgery or completion of radiation therapy ≤4 weeks prior to enrollment or radiation therapy that included >30% of the bone marrow.
22. 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).
23. Has had an allogeneic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Dose escalation: Incidence of DLTs (dose-limiting toxicities).
2. Expansion cohort: ORR by Investigator, defined as the proportion of participants who have achieved a confirmed BOR of CR or PR per RECIST version 1.1.

Secondary endpoints 10

1. Escalation: Incidence and severity of AEs graded according to the NCI CTCAE v5.0 and changes in clinical laboratory parameters, vital signs and ECGs. Incidence of dose interruptions, dose modifications and discontinuations due to AEs.
2. Escalation: ORR, DOR, PFS, DCR and TTR by Investigator.
3. Escalation: Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable), including but not limited to Cmax, Tmax, and AUC.
4. Escalation: Plasma PK parameters of encorafenib including but not limited to Cmax, Tmax, and AUC.
5. Expansion: DOR, PFS, DCR and TTR by Investigator.
6. Expansion: Incidence and severity of AEs graded according to the NCI CTCAE v5.0 and changes in clinical laboratory parameters, vital signs and ECGs. Incidence of dosing interruptions, dose modifications and discontinuations associated with AEs.
7. Expansion: Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable), including but not limited to Cmax, Tmax, and AUC.
8. Expansion: Plasma PK parameters of encorafenib including but not limited to Cmax, Tmax, and AUC.
9. Expansion: Plasma PK parameters of ZN-c3 including but not limited to Cmax and AUC.
10. Expansion: BRAF V600E mutational status.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

K-Group Beta Inc.

Sponsor organisation

K-Group Beta Inc.

Address

10835 Road To The Cure Suite 205

City

San Diego

Postcode

92121-1123

Country

United States

Scientific contact point

Organisation

K-Group Beta Inc.

Contact name

Meenakshi Rao

Public contact point

Organisation

K-Group Beta Inc.

Contact name

Meenakshi Rao

Third parties 3

Locations

5 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 79 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications