A Phase II Trial of AZD1775 plus Carboplatin-Paclitaxel in Squamous Cell Lung Cancer

Inclusion Criteria

• Provision of informed consent prior to any study specific procedures
• Histologic or cytological diagnosis of SQCLC with advanced/metastatic stage, with no known curative treatment options; prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation therapy given for locally advanced disease is considered first line therapy only if recurrent (local or metastatic) disease developed within 6 months of completing therapy; subjects with recurrent disease > 6 months from completion on chemotherapy will be eligible
• Eastern Cooperative Oncology Group (ECOG) performance status of 0/1
• Prior chemotherapy in the adjuvant/neoadjuvant/consolidation setting is allowed
• Any prior palliative radiation must have been completed at least 7 days prior to the start of studies drugs and patients must have recovered from any acute adverse effects prior to the start of the study treatment
• Prior immunotherapy with PD1i, PDL1i, anti-CTLA-4 or vaccines is allowed
• Leukocytes >= 3,000/uL
• Absolute neutrophil count >= 1,000/uL
• Platelets >= 100,000/uL
• Total bilirubin =< 1.5 X normal institutional limits (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal, or =< 5 X institutional upper limit of normal for patients with liver metastases
• Creatinine =< 2.0
• Have archival tissue available or undergo a fresh biopsy where clinically feasible after discussion with the sponsor
• No reproductive toxicology nor teratogenic studies have been conducted with AZD1775 to date, and it is unknown whether the drug is excreted in human milk; therefore, women of childbearing potential and men should agree to use adequate contraception prior to study entry and for the duration of study participation and women who are breast feeding are excluded from the study. Both women and men should be fully informed of the lack of reproductive toxicity testing, and women must have a negative pregnancy test prior to enrollment
• Female patients are considered to be of childbearing potential unless: * They are post-menopausal (defined as older than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments) * There is documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy (but not tubal ligation), or * They are 50 years or younger but have been amenorrheic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels in the postmenopausal range for the institution ** Female patients who are of childbearing potential must agree to use adequate contraceptive measures (as defined below) for the duration of study participation, and for 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician; they also may not be breast feeding and must have a negative serum or urine pregnancy test within 72 hours prior to start of study treatment ** Male patients who are sexually active with a female partner of childbearing potential must be either surgically sterilized or agree to use barrier contraception (i.e., condoms) for the duration of study participation, and for 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician
• Female patients who are of child-bearing potential (as defined above) should use enhanced methods of contraception from the time of screening until 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician; acceptable methods of contraception include true abstinence in line with the preferred and usual lifestyle choice of the subject, tubal ligation, vasectomized partner, and methods listed in the table below; all methods of contraception (with the exception of total abstinence) should be used in combination with the use of a condom by their male sexual partner for intercourse; periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Effective methods of contraception: * Barrier methods ** Cap plus spermicide ** Sponge plus spermicide ** Diaphragm plus spermicide * Intrauterine device methods ** Copper T ** Levonorgestrel-releasing intrauterine system (e.g., Mirena); this is also considered a hormonal method * Hormonal methods ** Any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular agents) such as *** Implants *** Hormone shot or injection *** Combined pill *** Minipill *** Patch
• Male patients should be asked to avoid unprotected sex with all sexual partners but use condoms plus spermicide during the study, and for a washout period of 90 days after the last dose of study drug; where a sexual partner of a male participant is a woman of child-bearing potential, patients should avoid procreation for 90 days after completion of study drug treatment; patients should refrain from donating sperm from the start of dosing until 90 days after discontinuing study treatment; if male patients wish to father children they should be advised to arrange for freezing of sperm samples prior to the start of study treatment

Exclusion Criteria

• Progressive, symptomatic untreated brain metastases
• Pregnancy or breast feeding
• A serious uncontrolled medical disorder or active infection that in the investigator’s opinion would impair the patient’s ability to receive study treatment
• Prior use of platinum or paclitaxel for stage IV non-small cell lung cancer (NSCLC) or concurrent use of other anticancer approved or investigational agents
• Use of anti-cancer treatment drug =< 21 days or 5 half-lives (whichever is shorter) prior to the first dose of AZD1775; for drugs for which 5 half-lives is =< 21 days, a minimum of 10 days between termination of the prior treatment and administration of AZD1775 treatment is required
• Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures =< 7 days; no waiting period required following port-a-cath or other central venous access placement
• Grade > 1 toxicity from prior therapy; EXCEPT: Alopecia, anorexia, and/or endocrinopathies on replacement therapy.
• Unable to swallow oral medications; Note: Patient may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN).
• Patients with known hepatitis B or C or human immunodeficiency virus (HIV) infection
• Second primary malignancy, other than in situ malignancies or adequately treated basal cell carcinoma of the skin or other malignancy treated at least 2 years previously with no evidence of recurrence
• Any of the following cardiac diseases currently or within the last 6 months: unstable angina pectoris, acute myocardial infarction, congestive heart failure >= class 2 (as defined by New York Heart Association [NYHA]), conduction abnormality not controlled with pacemaker or medication, significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible
• Patient has had prescription or non-prescription drugs or other products (i.e., grapefruit juice) known to be sensitive to cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4, which cannot be discontinued 2 weeks before day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug
• Co-administration of aprepitant and fosaprepitant during this study is prohibited
• AZD1775 is an inhibitor of breast cancer resistance protein (BCRP); the use of statins including Atorvastatin which are substrates for BCRP are therefore prohibited and patients should be moved on to non-BCRP alternatives
• Herbal preparations are not allowed throughout the study; these herbal medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
• History of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected
• Mean resting corrected QTc interval using the Fridericia formula (QTcF) > 450 msec/male and > 470 msec/female (as calculated per institutional standards) obtained from 1 electrocardiogram (ECGs)