| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Relapsed or Refractory Small Cell Lung Cancer (SCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with Relapsed or Refractory Small Cell Lung Cancer (SCLC) |
|
| 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 | LLT |
| E.1.2 | Classification code | 10025044 |
| E.1.2 | Term | Lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041070 |
| E.1.2 | Term | Small cell lung cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the objective response rate (ORR) of each arm |
|
| E.2.2 | Secondary objectives of the trial |
-To determine the duration of response (DOR) for each arm
-To evaluate the progression-free survival (PFS) for each arm
-To evaluate the OS for each arm
-To determine the disease control rate (DCR) for each arm
-To evaluate the safety and tolerability of KRT-232 for each arm
-To determine the pharmacokinetic (PK) profile of KRT-232 for each arm
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects ≥18 years of age and able to provide informed consent
2. Histologically or cytologically confirmed diagnosis of SCLC documented as TP53WT.
3. Disease must be measurable, with at least 1 measurable lesion per RECIST Version 1.1 (Appendix 4)
4. Subjects have evidence of radiographic progression during or after at least one prior platinum-containing therapy with no curative therapy available. Subjects who have received only one prior line of therapy must not be candidates for platinum-based regimens at relapse.
5. Subjects must have received a checkpoint inhibitor (PD-1 or PD-L1) unless contraindicated if checkpoint inhibitors are approved and available.
6. Adequate hematologic function independent of growth factor support for at least 7 days with the exception of pegylated granulocyte-colony stimulating factor (G-CSF) which require at least 14 days, defined as:
a. ANC ≥ 1.0 x 109/L
b. Platelet count ≥100 x 109/L
7. Adequate hepatic function with 28 days prior to the first dose of study treatment defined as:
a. Total serum bilirubin within normal limits. If total bilirubin is > upper limit of normal (ULN), then subjects are eligible if the direct bilirubin is ≤2.0 x ULN
b. Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN
8. Adequate renal function within 28 days prior to first dose of study treatment defined as an estimated creatinine clearance ≥30 mL/min by Cockcroft Gault
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
10. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use a highly effective contraception method during the study (Appendix 2). In addition, after the last dose of study drug, female subjects must continue to use a highly effective method of contraception for 1 month and 1 week and male subjects must continue to use a highly effective method of contraception for 3 months and 1 week. A woman is considered of childbearing potential (ie, fertile, following menarche and until becoming post-menopausal) unless permanently sterile (Appendix 2). |
|
| E.4 | Principal exclusion criteria |
1. Symptomatic or uncontrolled central nervous system (CNS) metastases. Subjects will not be excluded if they have received definitive local treatment and have documentation of stable or improved CNS disease based on brain imaging within 28 days prior to first dose of study drug, with adequately controlled symptoms, off or on a stable dose of corticosteroids (prednisone ≤10 mg daily or equivalent).
2. Prior treatment with MDM2 inhibitors
3. Chemotherapy, immune therapy, cytokine therapy, or any investigational therapy within 14 days prior to the first dose of study treatment
4. Active participation in other therapeutic clinical trials, including supportive care trials
5. Uncontrolled clinically significant cardiac disease (New York Heart Class III or IV), symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, history of myocardial infarction within 3 months
6. Grade 2 or higher QTc prolongation >480 msec per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
7. History of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks prior to the first dose of study treatment
8. History of another malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
9. History of major organ transplant
10. Known active hepatitis B or C infection
11. Known infection with human immunodeficiency virus
12. Clinically significant bacterial, mycobacterial, fungal, parasitic, or viral infection. IV antibiotics within 2 weeks prior to first dose of study treatment
13. Known hypersensitivity to or contraindications to the study drug or any of its excipients, or to required prophylaxes
14. Major surgery or planned major surgery within 21 days prior to first dose of study treatment
15. History of difficult swallowing, gastric or small bowel surgery with history of malabsorption or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the study treatment
16. Women who are pregnant or breastfeeding
17. Medical condition, serious intercurrent illness, psychiatric condition, or other circumstance (ie, committed to an institution by judicial or administrative authority) that, in the Investigator's judgment, could jeopardize the subject's safety, or that could interfere with study objectives |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Investigator assessed response per RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 6 weeks (± 7 days) for the first 12 months, then every 9 weeks (± 7 days) thereafter until disease progression or discontinuation from study. Complete response (CR) and partial response (PR) must be confirmed no less than 4 weeks from the time the initial
response was observed. |
|
| E.5.2 | Secondary end point(s) |
1.DOR among subjects who achieve a response, defined as the time from the initiation of response to disease progression or death.
2.PFS defined as the time from first dose date to disease progression or death
3.OS defined as the time from first dose date to death
4.Investigator-assessed response (of stable disease or better at any time while on study) per RECIST 1.1
5.• Incidence, nature and severity of adverse events (AEs) and serious adverse events (SAEs)
• Changes in laboratory values, ECGs and vital signs
6.KRT-232 and acyl glucuronide metabolite (M1) PK parameters, including but not limited to:
• maximum observed concentration (Cmax)
• minimum observed concentration (Cmin)
• area under the plasma concentration-time curve (AUC)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints are timeframe up to 7 study-week, or 12 study-week for subjects continuing on study beyond Cycle 3 |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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 | Yes |
| 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 | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Australia |
| Canada |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The study will be considered complete approximately 12 months after the last subject is enrolled, at which time subjects will be evaluated for eligibility for a rollover study that allows continued study drug access and long-term follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
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