| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| EGFR Mutation-Positive Non-Small Cell Lung Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-small cell lung cancer is a disease in which malignant (cancer) cells form in the tissues of the lung |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1:
To evaluate the safety profile of escalating doses of CK-101 and to determine the MTD and RP2D.
Phase 2:
To evaluate tumor response based on objective response rate (ORR) in patients with EGFR T790M mutation. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
- To characterize the pharmacokinetic (PK) profile of CK-101,
- To evaluate the effects of CK-101 on the QT/QTc interval,
- To profile circulating metabolites of oral CK-101 at steady state at the RP2D,
- To evaluate tumor response (objective response rate [ORR], disease control rate [DCR] and duration of response [DoR]) of CK-101
Phase 2:
- To evaluate the toxicity and tolerability of CK-101 at the RP2D,
- To evaluate tumor response based on disease control rate (DCR), duration of response (DoR) and tumor shrinkage in patients with EGFR T790M mutation,
- To evaluate progression-free survival (PFS) in patients with EGFR T790M mutation. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All patients enrolling into either Phase 1 or Phase 2 must meet all of the following inclusion criteria:
• Written consent on an IRB-approved Informed Consent Form (ICF) prior to any study-specific evaluation.
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements. Phase 2 patients: if only one measurable lesion exists, it is acceptable to be used as long as it has not been previously irradiated and baseline tumor assessment scans are done at least 14 days after the screening biopsy is performed.
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• Age ≥18 years
• Adequate hematological and biological function, confirmed by the following laboratory values:
Bone Marrow Function
− Absolute neutrophil count (ANC) ≥1.5 x 109/L
− Platelets ≥100.0 × 109/L
− Hemoglobin ≥9 g/dL (or 5.6 mmol/L)
Hepatic Function
− Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN); or ≤5 × ULN if liver metastases
− Bilirubin ≤1.5 × ULN; or ≤3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) or liver metastases
Renal Function
− Serum creatinine ≤1.5 × ULN
Patients enrolling into Phase 1 also meet the following inclusion criteria:
Histologically or cytologically confirmed diagnosis of any one of the following:
• Metastatic or unresectable locally advanced, recurrent NSCLC:
− with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q, T790M); or
− whose disease has not progressed after four cycles of platinum-based first-line chemotherapy (maintenance); or
− after failure of at least one prior chemotherapy regimen and immunotherapy; or
− EGFR WT patients and patients with non-sensitizing EGFR mutations as a later line of treatment.
• Any refractory solid tumor setting where targeting EGFR may be reasonable, for example:
− Treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer; or
− KRAS wild-type adenocarcinoma of the colon or rectum that is metastatic and/or unresectable; or
− Squamous cell carcinoma of the head and neck.
For Phase 1 EGFR mutation-positive NSCLC expansion cohorts ONLY, patients enrolling must also meet the following inclusion criteria:
• Histologically or cytologically confirmed diagnosis of one of the following:
− Metastatic or unresectable locally advanced NSCLC:
with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample; and
treatment naïve for locally advanced or metastatic NSCLC. Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents), however, prior exposure to an EGFR TKI is not permitted.
OR
− Metastatic or unresectable locally advanced NSCLC:
with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and
with evidence of radiological disease progression following 1st line EGFR TKI (i.e., 1st line treatment for advanced/metastatic disease) without any further treatment; and
with documented evidence of EGFR T790M mutation determined by PCR-based testing of the tumor tissue or plasma sample following disease progression on 1st line treatment with an EGFR TKI.
Patients enrolling into Phase 2 must also meet the following inclusion criteria:
• Histologically or cytologically confirmed metastatic or unresectable locally advanced, recurrent NSCLC; and
• Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI (e.g., gefitinib, erlotinib or afatinib). In addition other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study; and
• Documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and
• Documented evidence of EGFR T790M mutation determined by PCR-based testing of the tumor tissue using Sponsor central lab following disease progression on most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). |
|
| E.4 | Principal exclusion criteria |
Any of the following criteria will exclude patients from study participation:
• Active second malignancy or other prior malignancy treated with chemotherapy ≤ 6 months prior to treatment with CK-101.
• History of interstitial lung disease or evidence of clinically active interstitial lung disease.
• Brain metastases unless asymptomatic, stable and not requiring steroids for ≥ 2 weeks.
• Treatment with any of the following:
− An EGFR TKI (erlotinib, gefitinib, neratinib, afatinib, dacomitinib, osimertinib) within 3 days of the first dose of CK-101.
− Any cytotoxic chemotherapy, investigational agent or other anti-cancer drugs from a previous treatment regimen or clinical study within 14 days of the first dose of CK-101.
− Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of CK-101 (palliative radiation treatment with a limited field of radiation is allowed up to 7 days prior to first dose of CK-101).
− Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of CK-101) medications known to be potent inhibitors of CYP2C8 and potent inhibitors of CYP3A4 (see Appendix E).
• Any toxicity related to prior treatment must have resolved to Grade 1 or less, with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
• Any of the following cardiac criteria:
− Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms (ECGs).
− Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec.
− Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval (see Appendix D).
• Surgical procedures ≤14 days prior to administration of CK-101. In all cases, the patient must be sufficiently recovered and stable before treatment administration.
• Females who are pregnant or breastfeeding.
• Refusal to use adequate contraception for fertile patients (females and males) for 6 months after the last dose of CK-101 (see Appendix C).
• Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (e.g., substance abuse, uncontrolled psychiatric condition, uncontrolled intercurrent illness including active infection, arterial thrombosis, and symptomatic pulmonary embolism).
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CK-101.
For patients enrolling into Phase 1 expansion cohorts and Phase 2, the following criteria will also exclude patients from study participation:
• Prior treatment with CK-101 or other third generation TKIs that target EGFR T790M mutation-positive NSCLC (e.g., rociletinib or osimertinib).
• Evidence that the tumor harbors an exon 20 insertion mutation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
The incidence of Grade 3 or 4 or greater adverse events (AEs) and clinical laboratory abnormalities defined as dose-limiting toxicities (DLTs)
Phase 2:
ORR per RECIST Version 1.1 as assessed by an independent central review of radiological information |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline (first dose) to 28 days after last dose. |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
- PK parameters including, but not limited to, area under the curve from time zero to time t (AUC0-t), AUC up to 24 hours (AUC0-24), AUC from time zero to infinity (AUC0-∞), maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T1/2), terminal elimination rate constant (z), volume of distribution at steady state after nonintravenous administration (Vss/F), and total plasma clearance at steady state (Clss/F) for CK-101,
- Change from baseline in QT/QTc interval,
- Metabolic profile in the plasma sample,
- ORR, DCR and DoR per Response Criteria in Solid Tumors (RECIST) Version 1.1
Phase 2:
- The incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities,
- DCR, DoR and tumor shrinkage per RECIST Version 1.1 as assessed by an independent central review of radiological information,
- PFS per RECIST Version 1.1 as assessed by an independent central review of radiological information |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline (first dose) to 28 days after last dose. |
|
| 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 | No |
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | 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 | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
| New Zealand |
| Russian Federation |
| Thailand |
| United States |
| Poland |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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