Non-Small Cell Lung Cancer

Primary Objective To evaluate the antitumor efficacy of oral single agent CO-1686 , as measured by objective response rate (ORR), when administered to patients with EGFRmutated,T790M positive, advanced non-small cell lung cancer (NSCLC) after tumor progression on one previous EGFR–directed TKI. Secondary Objectives To assess secondary measures of clinical efficacy: disease control rate (DCR), duration of response (DR), progression free survival (PFS), overall survival (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 pharmacokinetics (PK) of CO-1686 using population PK (POPPK) methods and explore correlations between PK, exposure, response, and/or safety findings.

CO-1686 Hydrobromide Film-Coated Tablets

CO-1686 Hydrobromide

Tablet

125 and 250

Primary Endpoints:
ORR according to Response Criteria in Solid Tumors (RECIST) Version 1.1 as determined by independent radiology review (IRR)

Secondary Endpoints:
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.

1. Histologically or cytologically confirmed metastatic or unresectable locally advanced,
NSCLC.
2. Disease progression confirmed by radiologic assessment while receiving treatment with the
first single agent EGFR-TKI (e.g., erlotinib, gefitinib, afatinib, or dacomitinib)
EGFRTKI treatment discontinued ≤ 30 days prior to planned initiation of CO-1686.
The washout period for an EGFR inhibitor is a minimum of 3 days.
No intervening treatment between cessation of single agent EGFR-TKI and planned initiation of CO-1686.
Previous treatment with <=1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent)
Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1
or less.
3. Documented evidence of a tumor with one or more EGFR mutations excluding exon 20
insertion.
4. Tumor with the T790M mutation, as confirmed by the central laboratory. Biopsy material
obtained from either primary or metastatic tumor tissue and sent to the central laboratory
must be within 60 days of dosing study drug and following disease progression on the first
EGFR-TKI.
5. Measureable disease according to RECIST Version 1.1.
6. Life expectancy of at least 3 months.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Age ≥18 years (in certain territories, the minimum age requirement may be higher e.g. age ≥20 years in Japan and Taiwan)
9. 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); if liver metastases, ≤5 × ULN
- Bilirubin ≤2 × ULN
Renal Function
- Serum creatinine ≤1.5 × ULN
Electrolytes
- Potassium and magnesium within normal range. Patients may receive supplements to meet this requirement.
10. Written consent on an Institutional Review Board/Independent Ethics Committee approved Informed Consent Form (ICF) prior to any study specific evaluation.

Any of the following criteria will exclude patients from study participation:

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.
a. 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. . Leptomeningeal carcinomatosis or other untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases, other than leptomeningeal disease, are eligible, provided they have been clinically stable without requiring increase in steroid dose for at least 4 weeks.
5. Treatment with prohibited medications [e.g., 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)
7. Prior treatment with CO-1686, or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR e.g. 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 ms

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. 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.
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 (e.g., 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.