| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Osteosarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or Refractory Osteosarcoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10039498 |
| E.1.2 | Term | Bone sarcomas |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1:
- To investigate the safety and tolerability, including identification of the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ZN-c3 in combination with gemcitabine
Phase 2:
- To evaluate the clinical activity of WEE1 inhibition by ZN-c3 in combination with gemcitabine in subjects with relapsed/refractory osteosarcoma as assessed by the event-free survival (EFS) at 18 weeks, per response evaluation criteria in solid tumors RECIST Guideline version 1.1 |
|
| E.2.2 | Secondary objectives of the trial |
- To further evaluate the clinical activity based on EFS according to RECIST Guideline version 1.1 and to determine median overall survival (OS) and OS at 12 months of ZN-c3 in combination with gemcitabine
- To further investigate the safety and tolerability of ZN-c3 in combination with gemcitabine
- To investigate the plasma pharmacokinetics (PK) of ZN-c3 (and its potential metabolites as applicable) when given in combination with gemcitabine |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Provision of written informed consent by subjects and/or their parents or legally authorized representatives; assent, when appropriate, will be obtained according to institutional guidelines.
2 Age ≥12 years old at the time of informed consent.
3 Body weight ≥40 kg.
4 Histologically documented relapsed or metastatic osteosarcoma, as confirmed at the local study site.
a) The disease must have failed standard therapy and there is no known curative therapy available, or any available standard of care therapy was not tolerated or was refused by the subject.
b) The Investigator must confirm that gemcitabine is an appropriate treatment approach.
c) Subjects may have had any number of prior therapies and prior treatment with gemcitabine is allowed.
5 Must have measurable disease according to RECIST Guideline version 1.1 criteria.
6 Eastern Cooperative Oncology Group (ECOG) performance scale (PS) ≤2 for subjects ≥16 years of age or Lansky PS ≥50 for subjects <16 years of age.
7 Adequate hematologic and organ function as defined by the following criteria:
a) Absolute neutrophil count (ANC) ≥1000/mm3.
b) Platelet count ≥100,000/mm3.
c) Hemoglobin ≥8 g/dL.
d) Creatinine clearance ≥60 mL/min.
e) Total serum bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN in the case of Gilbert’s Syndrome.
f) AST and ALT ≤ 3 × ULN or ≤5 × ULN for subjects with liver metastases.
8 Ability and willingness to take oral medication.
A Phase 1/2 Study of ZN-c3 in Osteosarcoma Version 4.0
Protocol Number: ZN-c3-003 14 June 2021
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9 Willingness to release archival tissue for research purposes or to undergo a tumor tissue biopsy prior to dosing on Cycle 1 Day 1 if ≥18 years old. Biopsy samples of tumor tissue should be obtained if, in the judgment of the Investigator, the procedure is considered to be free of unacceptable risk. If in the opinion of the investigator a tumor tissue biopsy is not free of unacceptable risk, eligible patients may be allowed onto the trial on a case-by-case basis after consultation with the sponsor.
10 Female subjects of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) test.
11 Female subjects of childbearing potential and male subjects must agree to use a highly effective method of contraception prior to the first dose and for 6 months after the last dose of ZN-c3 and/or gemcitabine
12 Willingness to practice adequate sun protection (use of sunscreen or sun-protective clothing or limitation of sun exposure).
13 Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1 Any of the following treatment interventions within the specified time frame prior to Cycle 1 Day 1:
a) Major surgery <28 days (the surgical incision should be fully healed prior to study drug administration).
b) Any chemotherapy <21 days or 5 half-lives (whichever is shorter).
c) Prior radiotherapy <14 days.
d) Any investigational drug therapy <28 days or 5 half-lives (whichever is shorter).
e) Inability to discontinue treatment with prescription or non-prescription drugs, or consumption of food and herbal supplements that are strong/moderate CYP3A4 inhibitors or strong CYP3A4 inducers at least 14 days prior to start the treatment.
2 Unresolved toxicity of Grade >1 attributed to any prior therapies (excluding Grade ≤2 neuropathy, alopecia, or skin pigmentation).
3 Prior therapy with a WEE1 inhibitor.
4 Known hypersensitivity to gemcitabine or its excipients.
5 Known hypersensitivity to any drugs similar to ZN-c3 in class
6 A serious illness or medical condition(s) including, but not limited to, the following:
a) Brain metastases that require immediate treatment or are clinically or radiologically unstable (i.e., have been stable for <1 month). If receiving steroids,subjects must be receiving a stable dose or a decreasing corticosteroid dose during at least 1 week before enrollment.
b) Leptomeningeal disease that requires or is anticipated to require immediate treatment.
c) Myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart failure) resulting in heart failure by New York Heart Association Criteria (Class III or IV).
d) Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the subject inappropriate for entry into this study.
e) Significant gastrointestinal abnormalities, requirement for IV alimentation, active peptic ulcer, chronic diarrhea, or vomiting considered to be clinically significant in the judgment of the Investigator, or prior surgical procedures affecting absorption.
f) Active or uncontrolled infection. Subjects 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 before enrollment.
7 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.
8 Subjects with active (uncontrolled, metastatic) second malignancies or requiring therapy.
9 Individuals who are judged by the Investigator to be unsuitable as study subjects.
10 12-lead ECG demonstrating a corrected QT interval using Fridericia's formula (QTcF) of >470 ms, except for subjects with atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that render the QT measurement invalid.
11 History or current evidence of congenital or family history of long QT syndrome or Torsades de Pointes (TdP).
12 Taking medications with a known risk of TdP.
13 Administration of strong and moderate CYP3A4 inhibitors and inducers and P-gp inhibitors |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Incidence and severity of dose-limiting toxicities (DLTs) in DLT-evaluable subjects during Cycle 1 of Phase 1
2. EFS at 18 weeks (Phase 2) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Cannot be predicted as this study is to assess those parameters
2. Percentage cannot be predicted as this study is to assess this - the study will follow the Guideline for Osteosarcoma |
|
| E.5.2 | Secondary end point(s) |
1. Clinical activity:
According to RECIST Guideline version1.1 and clinical criteria:
- ΕFS
- OS (median and at 12 months)
2. Incidence and severity of adverse events (AEs) graded according to NCI common terminology criteria for adverse events (CTCAE), version 5.0
3. Plasma PK parameters of ZN-c3 (and its potential metabolites as applicable), including but not limited to maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve over the dosing interval |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Tumor imaging assess conducted prior to informed consent may be used for screening if they are collected within 28 days prior to Cycle 1 Day 1. Subsequent tumor imaging assess will be performed every 6 weeks (42 days) ± 4 days from Cycle 1 Day 1, and at the time of discontinuation.
2. Review on an ongoing basis.
3. Abbreviated ZN-c3 PK Sampling Time Points Day: Cycle 1 Day 15; 2 hours (± 10 min) post ZN-c3 admin; 4 hours (± 1 hour) post ZN-c3 admin; Cycles 2-6 Day 1. Collection Time Points : Pre-dose (within 0.5 hour prior to ZN-c3 admin) - Cycles 2-6 Day 1.
Disease Assessment will continue until confirmation of PD, initiation of the first subsequent cancer therapy, withdrawal of consent, death, loss to follow-up, or until the study is terminated |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| dose escalation and dose expansion |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| To investigate the safety and tolerability, including identification of the maximum tolerated dose |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Germany |
| Netherlands |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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