| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as erlotinib or gefitinib |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with EGFR mutant Non-Small Cell Lung Cancer who have failed treatment with an EGFR inhibitor |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029514 |
| E.1.2 | Term | Non-small cell lung cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025048 |
| E.1.2 | Term | Lung cancer non-small cell recurrent |
| 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 evaluate the toxicity profile of escalating doses of CO-1686 and to determine the MTD and RP2D
To characterize the PK profile of CO-1686
Phase 2:
To evaluate tumor response (ORR + duration of response) to CO-1686 in patients with T790M |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
To characterize the PK profile of CO-1686 after a high-fat breakfast vs in the fasted state
To evaluate the effects of CO-1686 on the QT/QTc interval
To evaluate tumor response (overall response rate [ORR]+duration of response) of CO1686
Phase 2:
To evaluate object response rate (ORR), duration of response, and progression-free survival [PFS] in patients treated with CO-1686.
To evaluate the toxicity and tolerability of CO-1686
To evaluate overall survival (OS) disease control rate (DCR) and progression-free survival [PFS] in patients treated with CO-1686
To characterize the pharmacokinetics (PK) of CO-1686 using population PK (POPPK) methods and explore correlations between PK, exposure, response, and/or safety findings
For a full list of secondary and exploratory objectives please see Protocol 7.1 Section . |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For Phase 1 and Phase 2:
•Histologically or cytologically confirmed metastatic or unresectable locally advanced, recurrent NSCLC
•Documented evidence of any activating mutation in the EGFR determined by either deoxyribonucleic acid (DNA) sequencing or polymerase chain reaction (PCR)-based testing of the NSCLC tumor using central laboratory assessment as documented evidence.
•Have undergone a biopsy of either primary or metastatic tumor tissue within 60 days of dosing study drug and have tissue available to send to sponsor lab or are able to undergo a biopsy during screening. No change (except for washout or dose adjustment if required to manage adverse effects) in antitumor therapy regimen is allowed between the biopsy and CO-1686 initiation.
•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 10e9/L
-Platelets >100.0 × 10e9/L
-Hemoglobin ≥9 g/dL (or 5.6 mmol/L)
Electrolytes
-Potassium and magnesium within normal range. Patients may receive supplements to meet this requirement
Hepatic Function
-Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN); if liver metastases, ≤5 × ULN
-Bilirubin ≤2 × ULN
Renal Function
-Serum creatinine ≤1.5 × ULN
•Written consent on an Institutional Review Board/Independent Ethics Committee-approved Informed Consent Form (ICF) prior to any study-specific evaluation
Patients enrolling into Phase 1 must also meet the following inclusion criteria:
•Prior treatment with EGFR-directed therapy (e.g. erlotinib, gefitinib, neratinib, afatinib, or dacomitinib [PF299804]). Prior chemotherapy, including intervening chemotherapy, is allowed.
-The washout period for an EGFR TKI is a minimum of 3 days.
-The washout period for chemotherapy is a minimum of 14 days.
-Any toxicity related to prior treatment must have resolved to Grade 1 or less.
•Be willing and able to eat a high-fat breakfast on Day 1 of the study (only applicable to food-effect cohort)
Patients enrolling into Phase 2 (Cohort A) must also meet the following inclusion criteria:
•Disease progression while on treatment with EGFR-directed therapy (e.g. erlotinib, gefitinib, neratinib, afatinib, or dacomitinib [PF299804]). Prior chemotherapy, including intervening chemotherapy before planned inititation of CO-1686, is allowed.
a) The washout period an EGFR TKI is a minimum of 3 days
b) The washout period for chemotherapy is a minimum of 14 days
- Any toxicity related to prior treatment must have resolved to Grade 1 or less
•Documented evidence of T790M mutation in EGFR determined by PCR-based testing of the tumor tissue using sponsor central lab following disease progression on most recent EGFR TKI therapy
•Measurable disease according to Response Criteria in Solid Tumors (RECIST) Version 1.1
• Do not qualify for enrolment to Phase 2 Cohort B*
*Patients meeting the eligibility criteria for Cohort B must be enrolled into Cohort B rather than Cohort A.
Patients enrolling into Phase 2 Cohort B must also meet the following inclusion criteria:
1.Disease progression while on continuous treatment with the first single agent EGFR-directed therapy (eg. erlotinib, gefitinib, afatinib, or dacomitinib [PF299804]) within the last 30 days, with no intervening treatment before planned initiation of CO-1686
a.The washout period for an EGFR TKI is a minimum of 3 days.
b.Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less.
2.Documented evidence of T790M mutation in EGFR as determined by PCR-based testing of tumor tissue using sponsor central lab following disease progression on the first single agent EGFR-directed therapy.
3.Measureable disease according to RECIST Version 1.1
4.≤ 1 prior line of chemotherapy
Patients with documented Gilbert’s syndrome and conjugated bilirubin within the normal range may be allowed into the study. In this event it will be documented that the patient was eligible based on conjugated bilirubin levels
Patients enrolling into Phase 2 Cohort C must also meet the following inclusion criteria:
• Must meet all inclusion criteria of either Phase 2 Cohorts A or B except for documented evidence of T790M mutation using sponsor central lab
• Only patients with evidence of a positive T790M mutation result from a local lab but with an insufficient specimen for central lab analysis (judged by the central lab analysis) or a negative central T790M mutation result from the same biopsy specimen collected within 60 days of treatment with CO-1686 |
|
| E.4 | Principal exclusion criteria |
Any of the following criteria will exclude patients from study participation:
•Documented evidence of an Exon 20 insertion activating mutation in the EGFR
•Active second malignancy, i.e. patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment.
- Patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy was completed >6 months prior and/or bone marrow transplant >2 years prior
•History of interstitial lung disease related to prior EGFR inhibitor therapy
•Patients with Leptomeningeal carcinomatosis are excluded. Other CNS metastases are only permitted if treated, asymptomatic, and stable (not requiring steroids for at least 4 weeks prior to start of study treatment).
•Treatment with prohibited medications (e.g., concurrent anticancer therapy including other chemotherapy, radiation therapy, or hormonal treatment [except corticosteroids and megesterol acetate], or immunotherapy) ≤14 days prior to treatment with CO-1686
•Prior treatment with CO-1686, or other drugs that target T790M positive, mutant EGFR with sparing of wild type EGFR, eg. AZD9291, HM61713, TAS-121
•Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia’s method (QTcF) >450 msec (males) or >470 msec (females),
•Family history of long QT syndrome
b. Inability to measure QT interval on ECG
c. Resting bradycardia < 55 beats/min
•Implantable pacemaker or implantable cardioverter defibrillator
•Treatment with any medication known to produce QT prolongation (see Appendix C for a partial list of prohibited medicines)
•Non-study related surgical procedures ≤ 7 days prior to administration of CO 1686. 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 CO-1686
•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)
•Any other reason the investigator considers the patient should not participate in the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
-The incidence of Grade 3 or 4 adverse events (AEs) and clinical laboratory abnormalities defined as dose-limiting toxicities (DLTs)
-PK parameters including area under the curve from time zero to time t (AUC0-t), AUC from time zero to infinity (AUC0-∞), maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T1/2), elimination rate constant (kel), volume of distribution at steady state after nonintravenous administration (Vss/F), and total plasma clearance (Cl/F) for CO-1686
Phase 2:
-ORR and duration of response per RECIST Version 1.1 by investigator assessment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
-PK parameters Cmax and AUC for CO-1686 (fasted and fed)
-Change from baseline in QT/QTc interval
-ORR and duration of response per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Exploratory Endpoints:
-Change from baseline in patient-reported outcomes
-Concordance of the presence of T790M mutation in blood and tumor tissue samples
-Detection of T790M in urine samples
Phase 2:
-ORR, duration of response and PFS per RECIST Version 1.1 as determined by independent radiology review (IRR)
-The incidence of AEs, clinical laboratory abnormalities, and electrocardiogram (ECG) abnormalities
-OS, DCR and PFS per RECIST Version 1.1 as determined by investigator assessment
-Plasma PK parameters for CO-1686 at Cycle 1 Day 1 and Cycle 1 Day 15 for a subset of patients; CO-1686 metabolite profile in the Day 15 plasma samples for a subset of patients; Plasma PK parameters for CO-1686 based on sparse sampling of all patients
-Change from baseline in patient reported outcomes
-Change from baseline in QT/QTc interval
Exploratory endpoints:
-Concordance of the presence of T790M mutation in blood and tumor tissue samples
-Detection of T790M in urine samples
-Time to treatment failure |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | 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 |
| First administration to humans of free base formulation, second administration of HBr formulation. |
|
| 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 | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| Poland |
| 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
|
| The trial will be completed when all enrolled patients have discontinued treatment and completed the end-of-study follow-up visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| 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 | 29 |
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