Studie indukční blokády PD-1 u subjektů s lokálně pokročilými solidními nádory s deficitem opravy nesouladu
Studie fáze II indukční blokády PD-1 u subjektů s lokálně pokročilými pevnými nádory s nedostatkem opravy nesouladu
The purpose of this study is to find out whether the study drug, TSR-042, followed by standard chemoradiotherapy (the chemotherapy drug capecitabine + radiation therapy) and standard surgery is an effective treatment for advanced dMMR solid tumors. The study will also look at the safety of the study drug.
Přehled studie
Postavení
Podmínky
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 2
Kontakty a umístění
Studijní kontakt
- Jméno: Neil Segal, MD, PhD
- Telefonní číslo: 646-888-4187
Studijní záloha kontaktů
- Jméno: Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
- E-mail: cerceka@mskcc.org
Studijní místa
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Connecticut
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Hartford, Connecticut, Spojené státy, 06102
- Nábor
- Hartford Healthcare (Data Collection)
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Kontakt:
- Gerard Fumo, DO
- Telefonní číslo: 860-972-4700
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Florida
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Miami, Florida, Spojené státy, 33143
- Nábor
- Baptist Alliance MCI (Data Collection Only)
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Kontakt:
- Antonio Ucar, MD
- Telefonní číslo: 786-373-3436
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New Jersey
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Basking Ridge, New Jersey, Spojené státy, 07920
- Nábor
- Memorial Sloan Kettering Basking Ridge - Limited Protocol Activities
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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Vrchní vyšetřovatel:
- Andrea Cercek, MD
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Middletown, New Jersey, Spojené státy, 07748
- Nábor
- Memorial Sloan Kettering Monmouth - Limited Protocol Activities
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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Montvale, New Jersey, Spojené státy, 07645
- Nábor
- Memorial Sloan Kettering Bergen - Limited Protocol Activities
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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New York
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Commack, New York, Spojené státy, 11725
- Nábor
- Memorial Sloan Kettering Commack - Limited Protocol Activities
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Vrchní vyšetřovatel:
- Andera Cercek, MD
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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Harrison, New York, Spojené státy, 10604
- Nábor
- Memorial Sloan Kettering Westchester - Limited Protocol Activities
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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New York, New York, Spojené státy, 10065
- Nábor
- Memorial Sloan Kettering Cancer Center
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Kontakt:
- Leonard Saltz, MD
- Telefonní číslo: 646-888-4181
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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Vrchní vyšetřovatel:
- Andrea Cercek, MD
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Uniondale, New York, Spojené státy, 11553
- Nábor
- Memorial Sloan Kettering Nassau - Limited Protocol Activities
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Kontakt:
- Andrea Cercek, MD
- Telefonní číslo: 646-888-4189
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Pennsylvania
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Allentown, Pennsylvania, Spojené státy, 18103
- Nábor
- Lehigh Valley Health Network (Data Collection Only)
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Kontakt:
- Maged Khalil, MD
- Telefonní číslo: 610-402-7880
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
Inclusion Criteria:
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Willing and able to provide written informed consent for the trial.
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Be ≥18 years of age on the date of signing informed consent.
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ECOG performance status of 0 or 1.
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Histologically confirmed locally advanced solid tumor (Cohorts 1 & 2)
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Histologically confirmed endometrial cancer (Cohort 3)
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Solid tumors that in standard practice would be treated with neoadjuvant therapy or surgery (depending on tumor type) (Cohorts 1 & 2)
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Endometrial cancer that is clinically FIGO 2009 Stage I or II (Cohort 3).
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No evidence of distant metastases.
- Radiologically measurable or clinically evaluable disease
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Tumor specimen that demonstrates mismatch repair deficiency by Immunohistochemistry or microsatellite instability as demonstrated by NGS or PCR.
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Negative pregnancy test done 72 hours prior to beginning treatment, for women of childbearing potential only. Subjects of childbearing potential must be willing to use an adequate method of contraception. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives, or double barrier method (diaphragm plus condom). Contraception, for the course of the study starting with the first dose of study medication through 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- For Cohort 3, the use of a combination estrogen/progesterone contraceptive is allowed; the use of progesterone-only methods including hormone (progestin) releasing IUD, depot medroxyprogesterone acetate, and progestin-only birth control pills is not allowed.
Nonchildbearing potential is defined as follows (by other than medical reasons):
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≥45 years of age and has not had menses for >1 year
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Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
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Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use 2 adequate barrier methods throughout the study.
- Participant receiving corticosteroids may continue if their dose is stable for least 4 weeks prior to initiating protocol therapy.
- Has QTcF ≤ 450 msec, or ≤ 480 msec for participants with bundle branch block.
- Demonstrate adequate organ function as defined below within 14 days of Cycle 1, Day 1, all screening labs should be performed within 14 days of treatment initiation.
- Hematological
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Absolute neutrophil count (ANC) ≥1,500 /mcL
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Platelets ≥100,000 / mcL
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Hemoglobin >9 g/dL or ≥5.6 mmol/L
- Renal
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Serum creatinine OR Measured or calculated(a) creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 × institutional ULN
- Hepatic
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Serum total bilirubin ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
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AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN
- Coagulation
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International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended (a) Creatinine clearance should be calculated per institutional standard.
Exclusion Criteria:
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Presence of metastatic or recurrent disease
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Prior radiation therapy, chemotherapy, or surgery for tumor
a. NOTE: For Cohort 3, patients are allowed to have received prior hormonal therapy for treatment of endometrial hyperplasia and/or endometrial cancer. Hormonal therapy must be discontinued at least 1-week prior to first dose of study treatment (dostarlimab).
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For patients with colorectal primary -Tumor is causing symptomatic bowel obstruction (patients who have a temporary diverting ostomy are eligible).
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Cohort 1 Only: Other invasive malignancy ≤ 5 years prior to registration. Exceptions are non-melanoma skin cancer that has undergone potentially curative therapy and in situ cervical carcinoma.
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Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of non- physiologic dose immunosuppressive therapy within 7 days prior to first dose of trial treatment.
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Active autoimmune disease requiring systemic treatment within the past 2 years or documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents at non-physiologic doses.
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Active infection requiring systemic therapy.
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Cohort 1 & 3: Received prior therapy with an antibody or drug specifically targeting T- cell co-stimulation or checkpoint pathways.
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Experienced ≥ Grade 3 immune-related AE with prior immunotherapy, except for non-clinically significant lab abnormalities.
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Other Anticancer or Experimental Therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibody or other experimental drugs) of any kind are permitted while the patient is receiving study treatment.
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Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
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Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
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Women who are pregnant or breastfeeding, or men expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening visit through 150 days after the last dose of study medication.
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Concurrent medical or psychiatric condition or disease which, in the investigator's judgement, would make them inappropriate candidates for entry into the study. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
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Received a live vaccine within 30 days of planned start of study medication.
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Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment.
a. NOTE: For Cohort 3: endometrial sampling (e.g., biopsies, dilatation and curettage), is NOT considered major surgical procedure.
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History of interstitial lung disease.
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Known hypersensitivity to TSR-042 components or excipients.
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Nerandomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Žádné (otevřený štítek)
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
|---|---|
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Experimentální: Cohort 1
Patients with clinical Stage II or Stage III MRI-staged, MSI-H or dMMR, solid tumors will receive up to 6 months (9, 21-day cycles) of PD-1 blockade followed by radiological and surgical restaging of the tumor. If subject exhibits complete clinical response, non-operative management will be followed. If a complete clinical response is not reached after 6 months of PD-1 blockade, the participant will proceed with standard chemoradiation. After completing chemoradiation participant will be assessed for response if complete CR is not obtained then the participant will proceed with disease specific surgical resection or standard of care therapy. |
Patients will be given TSR-042/Dostarlimab at a dose of 500mg IV, over 30 minutes Q 3 weeks.
Ostatní jména:
Capecitabine 825mg/m2 BID concurrently with radiation per standard radiation guidelines. If patient is unable to tolerate oral medication, infusional 5-FU is an acceptable alternative. The radiation dose is 5400 cGy to the tumor and surrounding nodes 4700 cGy to the pelvis, with an integrated boost to the primary tumor and involved nodes of receiving 5400cGy in 27fx. |
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Jiný: Cohort 2
The plan is to enroll six patients with MSI, regardless of their primary cancer diagnosis. This cohort will serve to generate hypothesis and initial data to plan a larger study. All analyses from this cohort will be exploratory |
Patients will be given TSR-042/Dostarlimab at a dose of 500mg IV, over 30 minutes Q 3 weeks.
Ostatní jména:
|
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Jiný: Cohort 3
Participants with FIGO Stage I or II mismatch repair deficient (MMRd) and/or microsatellite instability high (MSI-H) endometrial cancer will receive intravenous dostarlimab. |
Patients will be given TSR-042/Dostarlimab at a dose of 500mg IV, over 30 minutes Q 3 weeks.
Ostatní jména:
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Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Pathologic complete response (pCR) or complete clinical response (cCR) at 12 months
Časové okno: 12 months
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To determine the pathologic complete response rate (pCR) or complete clinical response (cCR) rate at 12 months, after PD-1 blockade and with or without chemoradiation in subjects with mismatch repair deficient locally advanced adenocarcinoma. |
12 months
|
Spolupracovníci a vyšetřovatelé
Spolupracovníci
Vyšetřovatelé
- Vrchní vyšetřovatel: Andrea Cercek, MD, Memorial Sloan Kettering Cancer Center
Publikace a užitečné odkazy
Obecné publikace
- Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, El Dika IH, Segal N, Shcherba M, Sugarman R, Stadler Z, Yaeger R, Smith JJ, Rousseau B, Argiles G, Patel M, Desai A, Saltz LB, Widmar M, Iyer K, Zhang J, Gianino N, Crane C, Romesser PB, Pappou EP, Paty P, Garcia-Aguilar J, Gonen M, Gollub M, Weiser MR, Schalper KA, Diaz LA Jr. PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer. N Engl J Med. 2022 Jun 23;386(25):2363-2376. doi: 10.1056/NEJMoa2201445. Epub 2022 Jun 5.
- Costa B, Vale N. Dostarlimab: A Review. Biomolecules. 2022 Jul 26;12(8):1031. doi: 10.3390/biom12081031.
- Cercek A, Foote MB, Rousseau B, Smith JJ, Shia J, Sinopoli J, Weiss J, Lumish M, Temple L, Patel M, Wilde C, Saltz LB, Argiles G, Stadler Z, Artz O, Maron S, Ku G, Gu P, Janjigian YY, Molena D, Iyer G, Coleman J, Abida W, Cohen S, Soares K, Schattner M, Strong VE, Yaeger R, Paty P, Shcherba M, Sugarman R, Romesser PB, Zervoudakis A, Desai A, Segal NH, El Dika I, Widmar M, Wei I, Pappou E, Fumo G, Aparo S, Gonen M, Gollub M, Jayaprakasam VS, Kim TH, Garcia Aguilar J, Weiser M, Diaz LA Jr. Nonoperative Management of Mismatch Repair-Deficient Tumors. N Engl J Med. 2025 Jun 19;392(23):2297-2308. doi: 10.1056/NEJMoa2404512. Epub 2025 Apr 27.
- Saude-Conde R, Nguyen D, Hendlisz A. Immunotherapies in non-metastatic gastrointestinal cancers. Curr Opin Oncol. 2023 Jul 1;35(4):334-346. doi: 10.1097/CCO.0000000000000956. Epub 2023 May 9.
Užitečné odkazy
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
- Urogenitální onemocnění
- Onemocnění genitálií
- Urogenitální novotvary
- Novotvary podle místa
- Novotvary
- Ženské urogenitální onemocnění
- Ženské urogenitální onemocnění a těhotenské komplikace
- Střevní nemoci
- Gastrointestinální novotvary
- Novotvary trávicího systému
- Nemoci trávicího systému
- Gastrointestinální onemocnění
- Kolorektální novotvary
- Střevní novotvary
- Rektální onemocnění
- Onemocnění dělohy
- Onemocnění pohlavních orgánů, ženy
- Genitální novotvary, ženy
- Novotvary dělohy
- Rektální novotvary
- Novotvary endometria
- Heterocyklické sloučeniny, 1 kruh
- Heterocyklické sloučeniny
- Terapeutika
- Nukleové kyseliny, nukleotidy a nukleosidy
- Deoxycytidin
- Cytidin
- Pyrimidinové nukleosidy
- Pyrimidiny
- Nukleosidy
- Uracil
- Pyrimidinony
- Radioterapie
- Deoxyribonukleosidy
- Radioterapie, konformní
- Radioterapie, asistovaná počítačem
- Kapecitabin
- Fluorouracil
- Radioterapie, modulovaná intenzita
- Dostarlimab
Další identifikační čísla studie
- 19-288
Plán pro data jednotlivých účastníků (IPD)
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Popis plánu IPD
Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.
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