Ficerafusp Alfa、ペムブロリズマブおよび定位放射線治療（SBRT）による頭頸部扁平上皮癌（HNSCC）の治療
フェセラフスプ・アルファ、ペンブロリズマブ、SBRTの術前併用療法による局所進行頭頸部扁平上皮癌（HNSCC）に対する第I/II相試験
The study is an open-label phase I/II clinical trial. The study will enroll patients to receive neoadjuvant SBRT plus 1 or 2 doses of neoadjuvant pembrolizumab with concurrent ficerafusp alfa (4 doses) prior to definitive surgical resection for high-risk, locoregionally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). Approximately 6 weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection followed by SOC adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. Adjuvant therapy is not part of this study and therefore is not dictated by study protocol.
調査の概要
状態
研究の種類
入学 (推定)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究連絡先
- 名前：Sana Karam, MD, PhD
- 電話番号：314-362-9700
- メール：sanadkaram@wustl.edu
研究連絡先のバックアップ
- 名前：Sidharth Puram, MD, PhD
- 電話番号：314-362-9700
- メール：sidpuram@wustl.edu
研究場所
-
-
Missouri
-
St Louis、Missouri、アメリカ、63110
- Washington University School of Medicine
-
副調査官：
- Peter Oppelt, MD
-
副調査官：
- Esther Lu, PhD
-
副調査官：
- Jesse Zaretsky, MD, PhD
-
コンタクト：
- Sana Karam, MD, PhD
- 電話番号：314-362-9700
- メール：sanadkaram@wustl.edu
-
コンタクト：
- Sidharth Puram, MD, PhD
- 電話番号：314-362-9700
- メール：sidpuram@wustl.edu
-
主任研究者：
- Sana Karam, MD, PhD
-
主任研究者：
- Sidharth Puram, MD, PhD
-
副調査官：
- Douglas R Adkins, MD
-
副調査官：
- Anthony J Apicelli, MD, PhD
-
副調査官：
- Christine Auberle, MD
-
副調査官：
- Jennifer De Los Santos, MD
-
副調査官：
- Hiram Gay, MD
-
副調査官：
- Lannis Hall, MD, MPH
-
副調査官：
- Yao Hao, PhD
-
副調査官：
- R Alex Harbison, MD, MS
-
副調査官：
- Ryan S Jackson, MD
-
副調査官：
- Brendan J Knapp, MD
-
副調査官：
- Daniel Miller, MD, PhD
-
副調査官：
- Patrick Pipkorn, MD
-
副調査官：
- Nikhil Rammohan, MD, PhD
-
副調査官：
- Jason T Rich, MD
-
副調査官：
- Robert D Siegel, MD
-
副調査官：
- Wade L Thorstad, MD
-
副調査官：
- Gregory R Vlacich, MD, PhD
-
副調査官：
- Paul Zolkind, MD
-
-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
-
Newly diagnosed histologically or cytologically confirmed locally advanced, OPC HPV-negative head and neck squamous cell carcinoma (OPSCC) or HNSCC arising from oral cavity, larynx, or hypopharynx.
-
Baseline resectable disease per the judgment of the treating surgical oncologist.
-
Clinical stage III, IVA, or IVB disease as defined using the 8th (2017) edition of the tumor, node, metastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC):
- T1-2, N1-3 or
- T3, any N or
- T4, any N
-
Documented tumor PD-L1 CPS ≥ 1 (by PD-L1 IHC pharmDx assay), determined locally.
-
Willing to provide blood and newly obtained core or excisional biopsy of tumor lesion pre-treatment and at the time of surgery for pathologic and correlative analyses.
-
Age 18 years or older at the time of informed consent.
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-
Adequate organ and marrow function as defined below:
- Absolute neutrophil count ≥ 1.5 K/cumm
- Platelets ≥ 100 K/cumm
- Hemoglobin ≥ 9 g/dL (without PRBC transfusion in the prior 7 days)
- Total serum bilirubin ≤ 1.5 x IULN (except for subjects with documented diagnosis of Gilbert syndrome). For subjects with a documented diagnosis of Gilbert's syndrome, total bilirubin must be ≤ 3.0 × ULN, provided that direct bilirubin is within normal limits
- AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
- Creatinine clearance (measured or calculated via the Cockcroft-Gault equation or per institutional standards) ≥ 30 mL/min
- PT/INR or aPTT ≤ 1.5 x IULN (except for subjects receiving anticoagulant therapy)
-
The effects of pembrolizumab and ficerafusp alfa on the developing human fetus are unknown. For this reason, people of childbearing potential and people able to father a child must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 120 days (women) or 90 days (men) after completion of study treatment.
-
Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.
Exclusion Criteria:
- Currently receiving any other investigational agents.
- Prior history of grade ≥ 2 intolerance or hypersensitivity reactions to other murine proteins, or the active substances of ficerafusp alfa, pembrolizumab, or any of their excipients.
- At higher risk of bleeding, including known bleeding diathesis or current active major bleeding, or recent major bleeding episode (within 4 weeks prior to enrollment).
- Any of the following within 6 months prior to starting study treatment: ST-elevation myocardial infarction, severe/unstable angina, uncontrolled cardiac ventricular arrhythmia, coronary/peripheral artery bypass graft or stent, cerebrovascular accident/stroke less than 6 months prior to enrollment, or congestive heart failure. Subjects with deep vein thrombosis who are hemodynamically stable can enroll if they are on a stable dose of anticoagulants for at least 3 months.
- Active autoimmune disease requiring systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Active systemic infection requiring either hospitalization or parenteral anti-infective therapy within 2 weeks before first dose of study treatment.
- Chronic hepatitis B virus (HBV) infection with active disease meeting the criteria for anti-HBV therapy but not on a suppressive antiviral therapy prior to initiation of study treatment. HBV testing not required in the absence of known history of infection. Note: Subjects who are hepatitis B surface antigen positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. These subjects should remain on antiviral therapy throughout the study treatment period and follow local guidelines for HBV antiviral therapy post completion of study treatment.
- Known history of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible provided they completed curative antiviral therapy at least 4 weeks prior to initiation of study treatment. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) with viral load >0 or CD4<350. HIV testing is not required in the absence of known history of infection.
- Receipt of any organ transplantation, including autologous and allogeneic stem cell transplantation, except for transplants that do not require immunosuppression.
- Known to be diagnosed and/or treated for any other additional malignancy within 2 years prior to randomization with the exception of the following: curatively treated basal cell carcinoma or squamous cell carcinoma of the skin, and curatively resected in situ cervical cancer, and curatively resected in situ breast cancer, and low-risk early stage prostate cancer defined as follows: Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study entry. Other exceptions may be considered with the PI's consultation. The time requirement for no malignancy for 2 years does not apply to the cancer for which a subject is enrolled in the study.
- Any condition requiring systemic treatment with either corticosteroids (>10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 7 days prior to the first dose of study treatment, except for topical, intranasal, intrabronchial, or ocular steroids. Corticosteroid use as premedication for allergic reactions (e.g., intravenous contrast), or as a prophylactic management of AEs related to the therapies specified in the protocol is allowed. The use of physiologic doses of corticosteroids may be approved after consultation with the principle-Investigator.
- Use of a live or live attenuated vaccine within 4 weeks prior to Screening. Note: Administration of killed, recombinant, or inactivated vaccines is allowed.
- Pregnant or breastfeeding. People of childbearing potential must have a negative pregnancy test at screening and within 7 days of first dose of study treatment.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：順次割り当て
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：Phase 1 Dose Level 1: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa
Treatment during the Phase 1 Level 1 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Days 1, 3, and 5), 2 doses of neoadjuvant pembrolizumab at 200 mg (given on D1 and D22), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. |
1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.
他の名前：
750mg intravenously (IV) on Days 1, 8, 15, and 22.
他の名前：
|
|
実験的：Phase 1 Dose Level -1: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa
Treatment during the Phase 1 Level -1 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Days 1, 3, and 5), 1 dose of neoadjuvant pembrolizumab at 200 mg (given on D1), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. |
1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.
他の名前：
750mg intravenously (IV) on Days 1, 8, 15, and 22.
他の名前：
|
|
実験的：Phase 1 Dose Level -2: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa
Treatment during the Phase 1 Level -2 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Days 1 and 4), 1 dose of neoadjuvant pembrolizumab at 200 mg (given on D1), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. |
1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.
他の名前：
750mg intravenously (IV) on Days 1, 8, 15, and 22.
他の名前：
|
|
実験的：Phase 1 Dose Level -3: Dose De-Escalation Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa
Treatment during the Phase 1 Level -3 consists of Stereotactic Body Radiotherapy (SBRT) at 8 Gy x 3 fractions over one week (given on Day 1), 1 dose of neoadjuvant pembrolizumab at 200 mg (given on D1), and 4 weekly doses of ficerafusp alfa at 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. |
1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.
他の名前：
750mg intravenously (IV) on Days 1, 8, 15, and 22.
他の名前：
|
|
実験的：Phase 2: Maximum Tolerable Dose (MTD) Neoadjuvant SBRT and pembrolizumab plus ficerafusp alfa
Treatment consists of SBRT beginning on D1 at the dose and number of fractions established in phase I, neoadjuvant pembrolizumab 200 mg at the number of doses established in phase I, and 4 weekly doses of ficerafusp alfa 750 mg (given on D1, D8, D15, and D22). Six weeks after end of SBRT, patients will undergo standard of care (SOC) surgical resection, or biopsy for patients who do not undergo resection, followed by standard of care (SOC) adjuvant chemoradiation per National Comprehensive Cancer Network (NCCN) guidelines. |
1-3 fractions given over 1 week as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II 200 mg intravenously (IV) given on Day 1 or Days 1 and 22 as assigned in phase I and as determined to be the maximum tolerated dose (MTD) in phase II.
他の名前：
750mg intravenously (IV) on Days 1, 8, 15, and 22.
他の名前：
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Phase I only: Maximum tolerated dose (MTD) of SBRT in combination with pembrolizumab plus ficerafusp alfa
時間枠：From start of treatment until date of surgery (total estimated time of 7 weeks)
|
The maximum tolerated dose (MTD) is defined as the highest dose level at which 0 or 1 patients of a cohort experience dose-limiting toxicity during the dose limiting toxicity (DLT) window. DLTs are defined in the protocol. |
From start of treatment until date of surgery (total estimated time of 7 weeks)
|
|
Phase II only: Rate of pathologic complete response (pCR)
時間枠：At the time of surgery (estimated to be week 7)
|
Response will be defined according to the systematic pTR system. pTR is defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor). pCR is defined as follows: 100% of sample characterized by tumor necrosis, keratinous debris, and/or giant cells/histiocytes |
At the time of surgery (estimated to be week 7)
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
第II相のみ：臨床的ダウンステージから病理学的ダウンステージへの変換率（および外科計画の修正の程度、該当する場合）
時間枠：外科手術時（第7週目と推定）において
|
外科手術時（第7週目と推定）において
|
|
|
Phase II only: Number and types of Adverse Events (AEs)
時間枠：From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
|
As defined by CTCAE v5.0. |
From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
|
|
Phase II only: Pathological response rate (PRR)
時間枠：At time of surgery (estimated to be week 7)
|
PRR is categorized as pCR, mPR, and others (pTR-0, pTR-1, pTR-2). Simon's two-stage optimal design will be used for a rate of pCR in phase II. Response will be defined according to the systematic pTR system. pTR is defined as the presence of tumor cell necrosis and keratinous debris with giant cell/histiocytic reaction, quantified as a percentage of the overall tumor bed (area pathologic response/area pathologic response plus viable tumor). pTR is defined as follows: pTR-0: < 10% of sample characterized by tumor necrosis, keratinous debris, and/or giant cells/histiocytes, pTR-1: 10-49%, pTR-2: 50-89%, pTR-3: 90-99% (also referred to as mPR), and pTR-4: 100% (also referred to as pCR). |
At time of surgery (estimated to be week 7)
|
|
Phase II only: Event-free survival (EFS)
時間枠：From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
|
EFS is defined as the time from the first date of treatment to the date of disease progression or death, whichever occurs first. |
From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
|
|
Phase II only: Overall survival (OS)
時間枠：From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
|
OS is defined as the time from the first date of treatment to the date of death. Alive patients are censored at the last follow-up otherwise. |
From start of treatment through 5 years after completion of treatment (estimated to be 5 years and 2 months)
|
協力者と研究者
捜査官
- 主任研究者：Sana Karam, MD, PhD、Washington University School of Medicine
- 主任研究者：Sidharth Puram, MD, PhD、Washington University School of Medicine
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- 202604179
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
米国で製造され、米国から輸出された製品。
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。