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 |
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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 |
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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 | 10029514 |
E.1.2 | Term | Non-small cell lung cancer NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate the antitumor efficacy of PO single agent CO-1686 , as measured by ORR, when administered to patients with EGFR-mutated, centrally confirmed T790M positive and T790 negative advanced NSCLC after tumor progression on 1 previous EGFR–directed TKI |
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E.2.2 | Secondary objectives of the trial |
• To assess clinical efficacy in patients with centrally confirmed T790M positive NSCLC: disease control rate (DCR), duration of response (DR), PFS, and OS following CO 1686 treatment • To assess quality of life (QoL) by patient-reported outcomes (PRO) following CO-1686 treatment • To evaluate the safety and tolerability of CO-1686 • To determine the pharmacokinetics (PK) of CO-1686 using population PK (POPPK) methods and explore correlations between PK, exposure, response, and/or safety findings
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Except where specified, inclusion criteria are applicable to both Cohorts A and B of the study. 1. Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC 2. Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion •Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR TKI (eg, erlotinib, gefitinib, afatinib, or dacomitinib) o EGFR TKI treatment discontinued ≤ 30 days prior to planned initiation of CO 1686 (the washout period for an EGFR inhibitor is a minimum of 3 days) o No intervening treatment between cessation of single agent EGFR TKI and planned initiation of CO 1686 o Previous treatment with ≤ 1 prior chemotherapy (excluding prior neo adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) o Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less • Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. Biopsy material obtained from either primary or metastatic tumor tissue must have been obtained (and sent to the central laboratory) within 60 days prior to dosing study drug but following disease progression on the first EGFR TKI. 3. Measureable disease according to RECIST Version 1.1 4. Life expectancy of at least 3 months 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 6. Age ≥ 18 years (in certain territories, the minimum age requirement may be higher, eg age ≥ 20 years in Japan and Taiwan) 7. Adequate hematological and biological function, confirmed by the following laboratory values: • Bone Marrow Function o Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L o Platelets > 100.0 × 10^9/L o Hemoglobin ≥ 9 g/dL (or 5.6 mmol/L) • Hepatic Function o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN); if liver metastases, ≤ 5 × ULN o Bilirubin ≤ 2 × ULN • Renal Function o Serum creatinine ≤ 1.5 × ULN • Electrolytes oPotassium and magnesium within normal range. Patients may receive supplements to meet this requirement 8. Written consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved ICF prior to any study specific evaluation
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E.4 | Principal exclusion criteria |
Except where specified, exclusion criteria are applicable to both Cohorts A and B of the study. 1. Documented evidence of an exon 20 insertion activating mutation in the EGFR gene 2. 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 3. Known pre existing interstitial lung disease 4. Cohort A only: Patients with leptomeningeal carcinomatosis are excluded. Other central nervous system (CNS) metastases are only permitted if treated, asymptomatic, and stable (not requiring steroids for at least 4 weeks prior to the start of study treatment). Cohort B only: Patients with CNS metastases or leptomeningeal carcinomatosis are excluded. 5. Treatment with prohibited medications (eg, concurrent anticancer therapy including other chemotherapy, radiation, hormonal treatment [except corticosteroids and megesterol acetate], or immunotherapy) ≤14 days prior to treatment with CO 1686 6. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting CO 1686 • see http://crediblemeds.org/ for a list of QT prolonging medications (includes all medication under categories of Known, Possible and Conditional risk of Torsades de Pointes) 7.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 8. Any of the following cardiac abnormalities or history: • Clinically significant abnormal 12 lead ECG, QT interval corrected using Fridericia's method (QTCF) > 450 msec • Inability to measure QT interval on ECG • Personal or family history of long QT syndrome • Implantable pacemaker or implantable cardioverter defibrillator • Resting bradycardia < 55 beats/min 9. Nonstudy 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 10. Females who are pregnant or breastfeeding 11. Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of CO 1686 12. Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, and symptomatic pulmonary embolism) 13. Any other reason the investigator considers the patient should not participate in the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR according to RECIST Version 1.1. For Cohort A, ORR will undergo independent radiology review (IRR) and in Cohort B, scans will be assessed by IRR if needed as a supporting analysis. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The ORR is the best overall response recorded from the start of the treatment until disease progression or recurrence. |
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E.5.2 | Secondary end point(s) |
• DR, DCR and PFS according to RECIST Version 1.1 as determined by IRR • ORR, DR, DCR and PFS according to RECIST Version 1.1 as determined by Investigator Assessment • OS • Change from baseline in patient reported outcomes using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C30), EORTC Quality of Life Questionnaire Lung Cancer module (EORTC QLQ LC13), and the Dermatology Life Quality Index (DLQI) • Treatment emergent adverse events (AEs), laboratory abnormalities and ECG abnormalities • Plasma PK parameters for CO-1686 based on sparse sampling
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From start of treatment until disease progression |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
single arm, open label, dual cohort clinical trial |
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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
| 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
Hong Kong |
Korea, Republic of |
Netherlands |
Spain |
Switzerland |
Taiwan |
United Kingdom |
United States |
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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
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Once study treatment has been discontinued and the End of Treatment visit has been completed, study participation will cease. Investigational centers will interpret tumor scans locally for the purpose of making treatment decisions and for final tumor response evaluation. The study will close once all patients have either completed participation, have transferred to a locally approved treatment access program in accordance with relevant local regulations or the sponsor decides to close the study. |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |