Phase 1Sstudy of Mmonotherapy with KHK2866, an Aanti-heparin-binding Eepidermal Ggrowth Ffactor-like Ggrowth Ffactor Mmonoclonal Aantibody, in Ppatients with Aadvanced Ccancer
John Sarantopoulos,Monica Mita,Michael J. Birrer, Lee D. Cranmer, Luis T. Campos, Xiaoping Zhang, Penelope Bristow, Hidekuni Kaito,Vincent Strout, Luis H. Camacho
Supplementary Mmaterials and Mmethods
Inclusion criteria
1)Patientsenrolled into:
Phase I dose-escalation cohorts
Histologically or cytologically documented, measurable or non-measurable, advanced primary or recurrent solid tumor which is unresponsive to standard therapy or for which there is no standard therapy available. Patients with histologically or cytologically advanced recurrent platinum-resistant epithelial ovarian cancer (EOC) must have received no more than two prior cytotoxic chemotherapy regimens. Chemotherapy regimens consisting of different platinum agents (e.g. cisplatin, carboplatin) and/or different taxane agents (e.g. paclitaxel, docetaxel) were all considered interchangeably as a single regimen (platinum/taxane). Prior treatment with biological agents (protein therapeutics produced in living cells) such as, but not necessarily limited to, bevacizumab, will not be counted as one of the two prior cytotoxic chemotherapy treatment regimens;
Phase 1maximum tolerated dose expansion cohort
Histologically or cytologically documented measurable or non-measurable: advanced recurrent platinum-resistant EOC with prior regimens limited as described for the phase Ia dose-escalation cohorts above; or locally unresectable and/or metastatic solid tumor of squamous histology without prior regimen restriction.
2)Patients with EOC were accepted as having platinum-resistant disease defined by either of the following criteria: patient did not respond or progressed during prior platinum-based chemotherapy; or patient relapsed within 6 months from completion of prior platinum-based chemotherapy.
3)Progressive and either unmeasurable or measurable disease during or following the last treatment regimen was defined by the Response Evaluation Criteria in Solid Tumors Version 1.1 guidelinesor by serum cancer antigen-125 (CA-125) greater than 2 the upper limit of normal (ULN) as defined by the Gynecologic Cancer Intergroup Criteria in the absence of measurable disease for patients with EOC. Patients with EOC qualifying on the basis of CA-125 greater than 2 ULN without measurable disease must nonetheless have evidence of non-measurable disease by imaging or physical examination. Ascites and pleural effusions were considered non-measurable disease.
4)Life expectancy >3 months.
5)Eastern Cooperative Oncology Group performance status score2 at study entry.
6)Age18 years.
7)Pre-study echocardiogram or multigated acquisition scan with left ventricular ejection fraction ≥50% or the institutional lower limit of normal, whichever is less.
8)Recovery to grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4 from the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other therapies for cancer with the exception of alopecia (for which no resolution is required) or peripheral neuropathy (which must have resolved to grade ≤2).
9)Preserved organ function evaluated within 7 days prior to the first dose of KHK2866:aspartate aminotransferase and alanine aminotransferase ≤2.5 ULN or ≤5.0 ULN in patients with metastatic liver disease; hemoglobin ≥9.0 g/dl (without transfusion in the preceding 7 days); total bilirubin ≤1.5 ULN; creatinine ≤1.5 mg/dl or calculated glomerular filtration rate according to the Cockcroft-Gault formula ≥60 ml/min; absolute neutrophil count ≥1.5109/l (unsupported by growth factors in the preceding 21 days); and platelets ≥100109/l (without transfusion or growth factor in the preceding 7 days).
10)Signed informed consent. Written informed consent must be obtained prior to performing any study-related procedures.
11)Women of childbearing potential (WOCBP) must have a negative pregnancy test at study entry. Females not considered WOCBP are those without menses for 24 consecutive months; and those who have undergone hysterectomy and/or bilateral salpingo-oophorectomy. WOCBP must be willing to use acceptable methods of birth control (i.e. a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide, or abstinence) for the duration of the study.
12)Males must use effective contraception (per the institutional standard) if procreative potential exists.
13)Any subject living alone must have a responsible adult that will be available to monitor, and communicate with the study site, the patient's mental/neurological status on a daily basis for the first week on study.
Exclusion criteria
1) Ovarian malignancy of low malignant potential.
2) Use of anticancer chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks prior to the first dose of KHK2866 (6 weeks for nitrosourea or mitomycin chemotherapy).
3) Use ofmonoclonal antibodies within 4 weeks of the first dose of KHK2866.
4) Major surgery within 4 weeks prior to the first dose of KHK2866.
5) Administration of a prohibited medication or treatment including: prophylactic use of erythroid-stimulating factors and granulocyte colony stimulating factors during the 28-day dose-limiting toxicity observation period (patients already receiving erythroid stimulating factors for chemotherapy-related anemia at the time of enrollment were permitted to continue to receive these agents without interruption); concurrent anticancer chemotherapy other than that specified in the protocol, hormonal therapy, or immunotherapy; radiation therapy during the first 28 days of treatment; biologic response modifiers; monoclonal antibodies other than KHK2866 or any other investigational agents whether for cancer or not; and concomitant use of anticonvulsant medications during the first 28 days of treatment.
6) History of brain metastases or primary brain neoplasm, even if previously treated and is stable neurologically.
7) History of leptomeningeal disease, even if previously treated.
8) Presence of epidural metastases, unless previously treated (e.g. surgery and/or radiation) and the epidural disease is considered by the investigator to be controlled.
9) Suspected impending bowel obstruction (including partial obstruction) based on clinical or radiographic data.
10) Pregnant (confirmed by beta human chorionic gonadotrophin) or lactating.
11) Significant uncontrolled intercurrent illness including, but not limited to: on-going or active infection requiring parenteral antibiotics; clinically significant cardiac disease (class II, III, or IV of the New York Heart Association classification); unstable angina pectoris, myocardial infarction within 6 months of planned treatment date, post coronary, or vascular angioplasty or stenting within 6 months; uncontrolled hypertension (i.e. systolic BP >150 mmHg, diastolic BP 90 mmHg) found on two consecutive measurements separated by a 1-week period; clinically significant cardiac arrhythmia as determined by the investigator; uncontrolled diabetes as determined by the investigator; serious or non-healing wound, ulcer, or fracture; history of cerebrovascular accident (thrombotic, embolic, and/or hemorrhagic) or transient ischemic attack; symptomatic head trauma within 12 months of planned treatment date; dementia or other disorders of mentation or dysphasia that could obscure the clinical evaluation of orientation, memory, higher mental function, and/or speech fluency/comprehension; and any seizure whether petit mal, tonic-clonic, or complex partial occurring within 12 months of planned treatment date.
12) Known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
13) Known active hepatitis B or C or other active liver disease.
14) Psychiatric illness, disability, or social situation that would compromise the patient’s safety, ability to provide consent, or limit his/her compliance with study requirements.
15) Known hypersensitivity reaction to monoclonal antibodies or other therapeutic proteins, and the reaction could not be controlled or prevented on subsequent infusion with standard therapies such as antihistamines, 5-HT3 antagonists, or corticosteroids.
16) History of second primary cancerexcept: curatively resected non-melanomatous skin cancer; curatively treated cervical carcinoma in situ; or other primary solid tumor treated with curative intent and no known active disease present and no treatment administered during the last 2 years.
17) History of interstitial lung disease or pulmonary fibrosis; radiographic findings consistent with interstitial lung disease on screening computerized tomography scan of the chest/lungs; arterial oxygen saturation <88% on room air at rest by pulse oximetry; and diffusion capacity for carbon monoxide <50% predicted unless there is tumor involvement of the thorax, pleura, or lung.
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