Ph II Trial to Assess Feasibility+Efficacy of Treatment w Durva+Treme+Radiation and Treatment w Durva+Radiation as First-line Therapy for Patients w Non-resectable Locally Advanced HPV-HNSCC- a Comparision With a Historical Control Group
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 18
- 试验地点
- 3
- 主要终点
- Efficacy- 1-year progression free survival (PFS)
研究概览
简要总结
Phase II trial evaluating to assess the feasibility and efficacy as first-line therapy for patients with non-resectable locally advanced HPV negative HNSCC of Durvalumab a PDL1-Inhibitor plus Tremelimumab a CTLA-4- Inhibitor in combination with radiotherapy and Durvalumab in combination with radiotherapy as first-line therapy.
2-arm, randomized, multicenter, phase II. Step 1 is Registration. All patients need to sign the informed consent form for registration. Tumor tissue then be send to the central lab for defining the HPV status. If the patient is HPV negative the site will be notified if they can further proceed to patient randomization.
Step 2 is Randomization of all eligible patients with a centrally diagnosed, HPV negative tumor in one of the two arms (Durvalumab plus Tremelimumab + radiotherapy; Durvalumab + radiotherapy) after signing the informed consent form for step 2.
详细描述
The primary objective is to explore the feasibility and efficacy in terms of treatment discontinuation due to toxicity and in terms of 1-year progression free survival of a PDL1-Inhibitor plus a CTLA-4 Inhibitor in combination with radiotherapy and a PDL1-Inhibitor in combination with radiotherapy as first-line therapy for patients with non-resectable locally advanced HNSCC in the poor prognostic subgroup.
Secondary objectives are to investigate the benefit of the addition of a CTLA-4 Inhibitor and/or a PDL1-Inhibitor to radiotherapy in terms of overall progression free survival, overall survival and to investigate the approach in terms of safety, chronic toxicity and quality of life.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with locally advanced histopathologically confirmed HNSCC not candidate for primary surgical treatment
- •No distant metastasis (M0)
- •Tumor tissue available for central testing Patient with HPV/p16 negative disease (≤70% positively stained cells) as determined by central testing
- •Adequate normal organ and marrow function
- •Measurable tumor according to RECIST
- •Patients must be expected to complete the treatment.
- •Age > 18 years at time of study entry
- •Female patients must either be of non-reproductive potential or must have a negative serum pregnancy test upon study entry and be willing to use adequate contraceptive measurements as described in the protocol
- •Non-sterilized males who are sexually active with a female partner of childbearing potential must be willing to use adequate contraceptive measurements as described in the protocol section 6.5.4
排除标准
- •Participation in another clinical study with an investigational product during the last 3 months
- •Prior or current anticancer treatment to the head and neck area (e.g. radical attempted or tumor reductive surgery, neo-adjuvant chemotherapy, EGFR inhibitors or radiotherapy).
- •Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
- •Patients with vitiligo or alopecia
- •Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
- •Any chronic skin condition that does not require systemic therapy
- •Patients without active disease in the last 5 years may be included but only after consultation with the study physician
- •Patients with celiac disease controlled by diet alone History of primary immunodeficiency
- •History of allogeneic organ transplant
- •History of another primary malignancy except for
- •Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- •Adequately treated carcinoma in situ without evidence of disease
- •History of hypersensitivity to durvalumab and/or tremelimumab or any excipient
- •Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
- •Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- •Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- •Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control as described in the protocol from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period
- •Distant metastasis
- •Patients who are institutionalised by official order
- •Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction
- •Receipt of live attenuated vaccination within 30 days prior to study entry step 2 or within 30 days of receiving durvalumab or tremelimumab
研究组 & 干预措施
Arm 1 - stopped after interims analyses
Patients in arm 1 will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy.
Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1).
干预措施: Durvalumab (Drug)
Arm 1 - stopped after interims analyses
Patients in arm 1 will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy.
Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1).
干预措施: Tremelimumab (Drug)
Arm 1 - stopped after interims analyses
Patients in arm 1 will receive a single dose of durvalumab of 1500 mg administered on day 1, 14 days prior to initiation of the radiotherapy.
Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14. On week 5, 9, 13 and 17 patients will receive durvalumab (1500 mg) and tremelimumab (75 mg) for up to 4 doses/cycles and then continue 1500 mg durvalumab q4w starting on week 21 to complete a total of 12 months of therapy (overall 9 single doses durvalumab including the initial dose on day 1).
干预措施: Radiotherapy (Radiation)
Arm 2
Patients in arm 2 will receive durvalumab (1500 mg) q4w starting on day 1. Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14.
Overall patients will receive treatment with durvalumab mono up to a total of 12 months (up to 13 doses in total).
干预措施: Durvalumab (Drug)
Arm 2
Patients in arm 2 will receive durvalumab (1500 mg) q4w starting on day 1. Radiotherapy with 35 fractions over 7 weeks (administered as daily fractions of 2 Gy given 5 days every week for 7 weeks) will start on day 14.
Overall patients will receive treatment with durvalumab mono up to a total of 12 months (up to 13 doses in total).
干预措施: Radiotherapy (Radiation)
结局指标
主要结局
Efficacy- 1-year progression free survival (PFS)
时间窗: 1 year
1-year progression free survival (PFS) depicted as the 1-year in-field-progression-free survival and 1-year distant metastasis free survival
Feasibility - Number of treatment discontinuations due to toxicity
时间窗: During treatment
number of treatment discontinuations due to toxicity
次要结局
- Overall Survival (OS)(From date of randomization until the date of death, assessed up to 3 years)
- Quality of life (QoL) - measured by EORTC QLQ-H&N35 and EORTC QLQ-C30)(From date of randomization until the date of study assessed up to 3 years)
- Safety - Number of participants with treatment-related adverse events as assessed by CTCAE v4.03(From date of randomization until the date of study assessed up to 3 years)
- Chronic toxicity -Number of participants with treatment-related adverse Events Lasting longer than 3 months as assessed by CTCAE v4.03 and/or RTOG/EORTC Late Radiation Morbidity Scoring Schema(From date of randomization until the date of study assessed up to 3 years)
研究者
Ulrich Keilholz
Director of the Charité Comprehensive Cancer Center, Principal Investigator, Clinical Professor
Charite University, Berlin, Germany