A Phase 2a, Multi-center, Open Label, Dose Optimization, Pilot Study to Assess the Safety and Tolerability at the Maximum Tolerated Dose of Parenteral TK-112690 in Non-Metastatic Squamous Cell Carcinoma of Head and Neck Patients Scheduled to Receive Chemoradiation.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- Tosk Inc
- 入组人数
- 30
- 试验地点
- 7
- 主要终点
- 2.MTD. Highest dose administered that is not associated with a DLT if three patients are treated or two or more DLTs if 6 patients are treated.
研究概览
简要总结
This is a multi-center, open label, dose optimization, pilot study to assess the safety, and tolerability at the maximum tolerated dose of Parenteral TK-112690 in non-metastatic squamous cell carcinoma of head and neck patients scheduled to receive chemoradiation.
A classic “3+3†design will be used to establish dose limiting toxicities (DLT), maximum tolerated dose (MTD). Three to six patients per treatment cohort will be assigned to receive sequentially escalating dose tiers of parenterally administered TK-112690 once for Day 1 to 5 (a “Cycleâ€), starting at a dose of 75mg/kg dose.
Cohort of three patients will be enrolled sequentially into escalating dose tiers of TK-90. Dose escalation will be conducted for each treatment group following a 3+3-design where cohorts of three patients will be treated per dose until the MTD is found at which no patient more than one out of three patients experience a DLT in the treatment course cohort. If one patients in a cohort experience a DLTs, another three patients will be enrolled in the same cohort; thus the DLT is defined as one patient out of three or two patients out of six patients . The starting dose for testing will be 75mg/kg. If there are no DLTs as defined above in the dose cohort, then the dose would be escalated by 15 mg/kg for 2nd, 3rd & 4th cohort. The maximum proposed TK-112690 dose is 120 mg/kg,.
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Expected ascending doses are 75, 90, 105 and 120 mg/kg.
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If DLT is observed at 75mg/kg cohort, the dose will be de-escalated to 60 mg/kg or 45 mg/kg in new patients following the same study design.
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Patients will remain for observation and PK sampling at the clinical site for a minimum of 8 hours post initial TK-112690 on Day 1 & Day 5 of Week 1
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If the TK-112690 is well tolerated and there are no safety concerns by end of Day 21(out of the 6 or 7 weeks cycle) post initial infusion, the second dose cohort will be initiated simultaneously. The treatment period for the study is 6-7 weeks.
Screening must be completed within 21 days of patient enrollment.
-Study follow-up will be scheduled post two weeks of completion of last dose of radiation or early termination through up to 4 weeks. If a patient has ulcerative SOM (WHO ≥ 3) at the last day of radiation therapy, visits for SOM will be repeated biweekly (at least 72 hrs apart) until the WHO score is 0 or 1 or the patient is 4 week’s post-radiation therapy, whichever occurs first.
-Weekly radiation treatments
o Patients will be treated for 5 consecutive days with a 2 Gy radiation treatment followed by a two-day treatment holiday.
o Prior to each radiation treatment the patients will receive a one-hour infusion of TK-90 (75 mg/kg) for Cohort 1 which will be escalated by 15 mg/kg for 2nd, 3rd & 4th cohort. the maximum proposed TK-112690 dose is 120 mg/kg
o At Day 3 of every radiation cycle, cisplatin as chemotherapy should be administered intravenously at a dose of 40 mg/m2. Cisplatin should be administered intravenously followed by the study medication administration and radiotherapy within 1 hour of the study medication administration, with pre-medications and adequate hydration protocol.
o This treatment cycle will continue for 6 -7 weeks.
o The final follow up will be conducted at Visit 10 (Week 9)
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Patients will receive TK-90 before 1 hour of the scheduled initiation radiation treatment.
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Standard safety evaluations will occur weekly during treatment.
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Mucositis assessment will be performed 2 times a week, i.e. Day 1 and Day 5 by PI, CO-Investigators, etc.
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PK sampling: At Treatment Week 1, Day1, blood samples will be collected pre-dose and then at 1, 2, 4, 6, and 8 hour’s post-dose after the administration of the first dose of the first cycle. At Day 2, Day 3, Day 4 blood samples will be collected prior to dosing and 1hr after dosing. At Day 5 blood samples will be collected pre-dose and then at 1, 2, 4, 6, and 8 hour’s post-dose after the administration. At Day 8 pre-dose sample will be collected
研究设计
- 研究类型
- Interventional
- 分配方式
- Not Applicable
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 75.00 Year(s)（—）
- 性别
- All
入选标准
- •Patient must sign study-specific Informed consent prior to study entry.
- •Male or Female patients aged 18 – 75 years.
- •Pathologically (histologically or cytologically) proven (from primary lesion and/or lymph nodes) diagnosis of squamous cell carcinoma of the oral cavity (Refer Definition in 10.13.1), oropharynx or hypopharynx.
- •Patients must have at least 1 mucosal site of the oral cavity/oropharynx/hypopharnyx mucosa assessable by visual transoral inspection that will receive cumulative radiation dose of 60-70 Gy. Note: Unavoidable doses of at least 60 Gy, to include entrance, exit, and scatter doses, still constitutes planned radiation.
- •Patients with tumors of the larynx or hypopharynx are eligible only if it is anticipated that at least 1 index site in the oral cavity/oropharynx/hypopharnyx mucosa (Refer section 10.13.1) will receive cumulative radiation dose of 60-70 Gy.
- •Patients with Stage I to III or IVA-B as per AJCC, Cancer Imaging Manual, 8th edition, at study entry, including no distant metastases other than non- metastatic SCCHN, based upon the following minimum diagnostic workup:.
- •History/physical examination, including documentation of tobacco/alcohol use and current medications (including opioids/dosing), within 8 weeks prior to enrollment.
- •PET /CT Scan/MRI within 8 weeks of enrollment.
- •Mucositis Grade ≤ 1 per WHO Scale and Xerostomia of Grade ≤ 2 per CTCAE version 5.
- •ECOG Performance Status ≤
- •Adequate bone marrow function as per CTCAE V 5, defined as follows (within 2 weeks prior to enrollment):.
- •Absolute neutrophil count ≥ 1500 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to enrollment.
- •Platelets ≥ 100,000 cells/mm3 based upon CBC obtained within 2 weeks prior to enrollment.
- •Hemoglobin ≥ 8.0 g/dl based upon CBC obtained within 2 weeks prior to randomization (Note: The use of transfusion or other intervention to achieve Hgb> 8.0 g/dl is acceptable).
- •Adequate hepatic function with bilirubin ≤ 1.5 x upper-normal limit (ULN), AST or ALT ≤3 x ULN within 2 weeks prior to enrollment.
- •Adequate renal function with serum creatinine < 1.5 mg/dl and creatinine clearance (CrC) ≥ 50 ml/min determined by 24-hour collection or estimated by Cockcroft-Gault formula. CrC male equals [(
- •age) x (wt in kg)] / [(Serum Cr mg/dl) x (72)]. CrC female equals 0.85 x (CrCl male) within 2 weeks prior to enrollment.
- •Negative serum pregnancy test for women of childbearing potential.
- •Women of childbearing potential and male participants with female partners of childbearing potential must practice adequate contraception.
排除标准
- •Stage IVC (Any T, Any N, M1) per AJCC Cancer Staging Manual.
- •8th ed, or distant metastases at protocol study entry.
- •Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years.
- •Patients who have not fully recovered after prior to SCCHN surgery.
- •(Except those Patients who have had prior surgery and have fully recovered and patients who may have surgery in the future are eligible).
- •Severe, active co-morbidity, defined as follows: -Symptomatic and/or uncontrolled cardiac disease, New York Heart Association Classification III or IV.
- •Transmural myocardial infarction within the last 6 months.
- •Acute bacterial or fungal infection requiring intravenous antibiotics at the time of screening.
- •Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of screening.
- •Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
- •Patients known to be sero-positive for human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV).
- •Concurrent available or experimental systemic or topical pharmaceuticals or devices or low-level laser therapy for OM.
- •Oral rinses—limited to sodium bicarbonate, lidocaine, and antifungal agents—will be permitted.
- •Supportive care per ASCO guidelines is permitted and encouraged.
- •Collagen vascular disease, such as scleroderma.
- •Previous treatment with palifermin or other keratinocyte growth factors, such as velafermin or repifermin, within a month of enrollment.
- •Any prohibited therapy 2 weeks prior to enrollment.
- •(see Section 8.4)
- •Pregnancy, breast feeding or women of childbearing potential and men who a sexually active and not willing/able to use medically acceptable forms of contraception.
- •Known hypersensitivity study medication or excipients in the formulation.
- •Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study.
- •The use of steroids during treatment.
结局指标
主要结局
2.MTD. Highest dose administered that is not associated with a DLT if three patients are treated or two or more DLTs if 6 patients are treated.
时间窗: 7 weeks
1.DLTs- Any grade ≥3 DLTs during study graded according to the CTCAE, v5.0 that cannot clearly be attributed to a cause other than TK-112690.
时间窗: 7 weeks
4.Incidence of radiation induced mucositis (RIM).
时间窗: 7 weeks
3.RP3D. Dose based on achieving a MTD or achieving a plasma concentration expected to be efficacious based on animal experiments with TK-112690.
时间窗: 7 weeks
次要结局
未报告次要终点