Phase-2 Dacomitinib Study on Patients With EGFR-Driven Advanced Solid Tumours With Low EGFR-AS1 IncRNA Expr or Other Novel Emerging Biomarkers

Inclusion criteria

• Provision of a voluntarily given, personally signed and dated, written informed consent document. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness;
• Age ≥ 21 years, male or female;
• Documentation of the presence of low EGFR-AS1 lncRNA expression as determined using the specifically designed companion diagnostic biomarker suite provided by the Sponsor (cohorts 1 to 3) or the presence of a novel emerging biomarker of EGFR family pathway addiction as determined by the Sponsor (cohort 4);
• Study cohorts:

• Cohort 1: advanced or metastatic EGFR wildtype squamous NSCLC, after progression on or after, or intolerance to, one or more lines of standard of care (SOC) therapy, per local SOC guidelines. In subjects without an activating oncogenic driver mutation, after progression on or after, or intolerance to, platinum-containing combination chemotherapy. In subjects harbouring an activating oncogenic driver mutation, after progression on one or more SOC mutation-targeting TKI, per local SOC guidelines, or for whom no SOC mutation-targeting TKI is available. TKI therapy need not be the most recent prior therapy. Subjects harbouring an activating EGFR mutation are not eligible;
• Cohort 2: advanced or metastatic head and neck squamous cell carcinoma, after progression on or after, or intolerance to, platinum-containing combination chemotherapy. This need not be the most recent or prior regimen;
• Cohort 3: all advanced or metastatic solid tumours (excluding squamous NSCLC and HNSCC), after progression on or intolerance to at least one line of SOC therapy per local guidelines;
• Cohort 4: all advanced or metastatic solid tumours, after progression on or intolerance to at least one line of SOC therapy per local guidelines;
• Have an ECOG PS of ≤2;
• Life expectancy of at least 3 months;
• Site of disease amenable to biopsy and be a candidate for tumour biopsy according to the treating institution's own guidelines and requirements for such procedure. Subjects must be willing to undergo a tumour biopsy at screening, and on treatment on this study;
• Radiologically measurable disease by RECIST v1.1 criteria:

• At least one target lesion that has not previously been radiated and is measurable according to RECIST v1.1;
• Acceptable radiologic procedures for disease assessment include contrast enhanced conventional or spiral computed tomography (CT), or contrast enhanced magnetic resonance imaging (MRI);Non contrast CT scan is acceptable only for subjects who are both allergic to intravenous contrast and unable to cooperate with MRI, or MRI is not available. The following are not allowed as sole documentation of target lesions: CT component of a positron emission tomography (PET)/CT, ultrasound alone, nuclear scans (including bone or PET scans), chest X-ray or bone radiographs, and tumour markers;
• Adequate organ function, including:

• Estimated creatinine clearance ≥30 mL/min (as determined by Cockcroft-Gault formula or the study site's standard formula);
• Absolute neutrophil count (ANC) ≥1500 cells/mm3;
• Platelets ≥100,000 cells/mm3;
• Hemoglobin ≥10.0 g/dL;
• Bilirubin ≤1.5 x upper limit of normal (ULN);
• Aspartate aminotransferase (AST; also known as SGOT) and Alanine aminotransferase (ALT; also known as SGPT) ≤2.5 x ULN (≤5.0 x ULN if hepatic metastases).
• Female subjects must be postmenopausal (defined as 12 months of amenorrhea following last menses), or they or their partners must be surgically sterile, or must agree to use effective contraception while receiving study treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the investigator using following criteria:

• Acceptable contraception for women include implants, injectables, combined oral contraceptives, intrauterine devices (IUDs), sexual abstinence, or a partner who has been surgically sterile (e.g. by vasectomy) for at least 6 months. Acceptable contraception for a male includes surgical sterility (e.g. by vasectomy) for at least 6 months, sexual abstinence, or condoms plus spermicide.
• All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) before starting study treatment;
• Male subjects or their female partners must be surgically sterile or must agree to use effective contraception while receiving study treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the investigator. Or female partners must be postmenopausal (defined as 12 months of amenorrhea following last menses);
• Willing and able to comply with study scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion criteria

• Subjects with symptomatic brain metastases or leptomeningeal metastases who are neurologically unstable or require increasing doses of steroids to manage central nervous system (CNS) symptoms within two weeks prior to starting dacomitinib;
• Any surgery (not including minor procedures such as lymph node biopsy), palliative radiotherapy or pleurodesis within 2 weeks of baseline assessments;
• Any clinically significant gastrointestinal abnormalities that may impair intake, transit or absorption of the study drug, such as the inability to take oral medication;
• Current enrollment in another therapeutic clinical study;
• Any psychiatric or cognitive disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this study or known drug abuse/alcohol abuse;
• History of, or currently suspected, diffuse non-infectious pneumonitis or interstitial lung disease including:

• Past medical history of interstitial lung disease, drug-induced interstitial disease, radiation pneumonitis which required steroid treatment or any evidence of clinically active interstitial lung disease;
• Pre-existing idiopathic pulmonary fibrosis evidenced by CT scan at baseline;
• Insufficient lung function as determined by either clinical examination or an arterial oxygen tension of <70 Torr.
• Any history of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption;
• Clinically important abnormalities in cardiac rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, second degree heart block, third degree heart block) OR:

• Diagnosed or suspected congenital long QT syndrome;
• Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
• Prolonged QTc interval on electrocardiogram (ECG); QTc must be less than CTCAEv5.0 Grade 2 (≤480 msec) using Fridericia's or Bazett's correction formula with a manual reading by the investigator if required. The ECG may be repeated for evaluation of eligibility after management of correctable causes for observed QTc prolongation;
• Any history of second- or third-degree heart block;
• Heart rate <45 beats per minute on ECG in the presence of clinical symptoms (e.g., hypotension, evidence of hypoperfusion);
• Severely impaired (defined as Child-Pugh Class C) hepatic dysfunction;
• Prior malignancy: Subjects will not be eligible if they have history of, or evidence of another concurrent malignancy within 2 years prior to registration. Exception would be effectively treated past history of non-melanoma skin cancer or in-situ cervical cancer with no evidence of active disease. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 2 years after definitive primary treatment;
• Other severe acute or chronic medical condition that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study;
• Use of narrow therapeutic index drugs that are CYP2D6 substrates (procainamide, pimozide, and thioridazine etc.) from screening to randomization.
• Active primary immunodeficiency, known HIV infection, or known active hepatitis B or C infection. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if:

• Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody [anti-HBc] positive; OR
• HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to be ≤2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases; OR
• HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with liver metastasis and abnormal transaminases alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) <3 upper limit of normal (ULN)
• Subjects with a history of hepatitis C infection will be eligible for enrolment only if the viral load according to local standards of detection is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (i.e., sustained viral response according to the local product label but no less than 12 weeks, whichever is longer) prior to the viral load evaluation.