A Phase II Randomized Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site

Cancer of Unknown Primary Site Clinical Trial

— CUPISCO  

Official title:

A Phase II, Randomized, Active-Controlled, Multi-Center Study Comparing the Efficacy and Safety of Targeted Therapy or Cancer Immunotherapy Guided by Genomic Profiling Versus Platinum-Based Chemotherapy in Patients With Cancer of Unknown Primary Site Who Have Received Three Cycles of Platinum Doublet Chemotherapy

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03498521
• Other study ID #: MX39795
• Secondary ID: 2017-003040-20
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: July 10, 2018
• Est. completion date: June 9, 2024

Study information

• Verified date: June 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study will compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in participants with poor-prognosis cancer of unknown primary site (CUP; non-specific subset) who have achieved disease control after 3 cycles of first-line platinum based induction chemotherapy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 528
• Est. completion date: June 9, 2024
• Est. primary completion date: February 14, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically-confirmed unresectable cancer of unknown primary site (CUP) diagnosed according to criteria defined in the 2015 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for CUP

• No prior lines of systemic therapy for the treatment of CUP

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Candidate for platinum-based chemotherapy (according to the reference information for the intended chemotherapy)

• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)

• Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue sample </= 4 months old that is expected to be sufficient for generation of a comprehensive genomic profile at a central reference pathology laboratory

Exclusion Criteria:

• Squamous cell CUP

• Participants who can be assigned to a specific subset of CUP for which a specific treatment is recommended by the 2015 ESMO Clinical Practice Guidelines for CUP or with a clinical and IHC profile indicative of a specific primary tumor (favorable prognosis CUP subsets): Poorly differentiated carcinoma with midline distribution; women with papillary adenocarcinoma of the peritoneal cavity; women with adenocarcinoma involving only the axillary lymph nodes; squamous cell carcinoma of the cervical lymph nodes; poorly differentiated neuroendocrine tumors; men with blastic bone metastases and elevated prostate-specific antigen (PSA); participants with a single, small, potentially resectable tumor; colon cancer-type CUP, including participants with a CK7 negative, CK20 positive, CDX-2 positive immunohistochemistry profile; CK7-positive, CK20-negative and TTF-1 positive tumors in a context suggestive of lung adenocarcinoma or thyroid cancer; IHC profile definitely indicative of breast cancer OR an IHC profile indicative of breast cancer and either a history of breast cancer or lymph nodes in the drainage areas of the breast; high-grade serious carcinoma histology and elevated CA125 tumor marker and/or a mass in the gynecological tract or any tumor mass or lymph node in the abdominal cavity; IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak classification higher than IIF; IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease or with only pulmonary metastases and/or lymph nodes in the drainage areas of the liver

• Known presence of brain or spinal cord metastasis (including metastases that have been irradiated only)

• Histology and immunohistology profiles (per 2015 ESMO guidelines) that are not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma

• History or known presence of leptomeningeal disease

• Known human immunodeficiency virus (HIV) infection

• Significant cardiovascular disease

• Prior allogeneic stem cell or solid organ transplantation

• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or for up to 7 months after the final dose of treatment

Related Conditions & MeSH terms

• Cancer of Unknown Primary Site
• Neoplasms, Unknown Primary

Intervention

Drug:
• Alectinib
Alectinib will be administered orally at the label-recommended dose (600 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Vismodegib
Vismodegib will be administered orally at the label-recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Ipatasertib
Ipatasertib will be administered orally at the label-recommended dose (400 mg) once daily on Days 1-21 of each 28-day Cycle in combination with paclitaxel, and as monotherapy after the final administration of paclitaxel, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Olaparib
Olaparib will be administered orally at the label-recommended dose (400 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Erlotinib
Erlotinib will be administered orally in combination with Bevacizumab at the label recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Bevacizumab
Bevacizumab will be administered intravenously at 15mg/kg every 3 weeks in combination with Erlotinib until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Vemurafenib
Vemurafenib will be administered orally, 960 mg twice daily, in combination with Cobimetinib, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Cobimetinib
Cobimetinib will be administered orally, 60mg once daily, in combination with Vemurafenib, on Days 1-21 of each 28-day Cycle, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Trastuzumab Subcutaneous (SC)
Trastuzumab will be administered subcutaneously, 600 mg every 3 weeks, in combination with Pertuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Pertuzumab
Pertuzumab will be initially be administered intravenously, 840 mg, followed by 420 mg every 3 weeks, in combination with Trastuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
• Atezolizumab
Atezolizumab will be administered intravenously at the label-recommended dose (1200 mg), alone or in combination with chemotherapy, every 3 weeks until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Carboplatin
Carboplatin will be administered intravenously at the area under the curve (AUC) dose once every 3 weeks for up to 9 Cycles (Cycle = 21 days) in some combination with the following: Paclitaxel, Gemcitabine, Atezolizumab, Pertuzumab, and Trastuzumab SC.
• Paclitaxel
Paclitaxel will be administered intravenously, 175 mg/m^2, once every 3 weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Carboplatin, Ipatasertib, Atezolizumab, Pertuzumab, and Trastuzumab SC
• Cisplatin
Cisplatin will be administered intravenously, 60-75 mg/m^2, once every three weeks, for up to 9 cycles (Cycle = 21 days) in some combination with the following: Gemcitabine, Paclitaxel, Atezolizumab, Pertuzumab, and Trastuzumab SC.
• Gemcitabine
Gemcitabine will be administered intravenously, 1000 mg/m^2, twice every three weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Cisplatin, Carboplatin, Atezolizumab, Pertuzumab, and Trastuzumab SC.
• Entrectinib
Entrectinib will be administered orally at the label-recommended dose (600 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
• Ivosidenib
Ivosidenib will be administered orally at the label-recommended dose (500mg) once daily across a 28-day treatment cycle until loss of clinical benefit or unacceptable toxicity.
• Pemigatinib
Pemigatinib will be administered orally at the label-recommended dose (13.5mg) once daily across a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.

Locations

Country	Name	City	State
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Peter MacCallum Cancer Center	North Melbourne	Victoria
Australia	Icon Cancer Foundation	South Brisbane	Queensland
Australia	Northern Cancer Institute	St Leonards	New South Wales
Austria	LKH-UNIV. KLINIKUM GRAZ; Klinische Abteilung für Onkologie	Graz
Austria	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg
Austria	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Chemotherapie & Infektionskrankhei	Wien
Brazil	Hospital de Cancer de Barretos	Barretos	SP
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Instituto Nacional de Cancer - INCa; Oncologia	Rio de Janeiro	RJ
Brazil	Hospital Sao Rafael - HSR	Salvador	BA
Brazil	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP
Bulgaria	MBAL Serdika EOOD	Sofia
Bulgaria	MHAT Nadezhda	Sofia
Chile	Bradford Hill Centro de Investigaciones Clinicas	Recoleta
Chile	James Lind Centro de Investigación Del Cáncer	Temuco
Colombia	Clinica del Country	Bogota
Colombia	Inst. Nacional de Cancerologia; Clinica de Seno	Bogota
Colombia	Oncomedica S.A.	Monteria
Croatia	Clinical Hospital Centre Zagreb	Zagreb
Czechia	Masarykuv onkologicky ustav	Brno
Czechia	Fakultni nemocnice Olomouc; Onkologicka klinika	Olomouc
Czechia	Fakultni Poliklinika Vseobecne Fakultni Niemocnice; Onkologicka Klinika	Praha 2
Denmark	Aarhus Universitetshospital; Afdeling for Eksperimentel Klinisk Onkologi	Aarhus N
Denmark	Rigshospitalet; Onkologisk Klinik	København Ø
Estonia	North Estonia Medical Centre, Oncology and hematology Clinic; Department of Chemotherapy	Tallinn
Finland	Helsinki University Central Hospital; Dept of Oncology	Helsinki
Finland	Tampere University Hospital; Dept of Oncology	Tampere
France	Ico - Paul Papin	Angers
France	CHRU Besançon	Besançon
France	Institut Bergonie; Oncologie	Bordeaux
France	CRLCC-Francois Baclesse; Oncologie Médicale	Caen
France	Centre Jean Perrin Centre Regional de Lutte Contre Le Cancer D auvergne	Clermont-ferrand
France	Centre Leon Berard	Lyon
France	Institut Paoli-Calmettes; Oncologie Medicale 1	Marseille Cedex 09
France	Institut régional du Cancer Montpellier	Montpellier
France	Centre Antoine Lacassagne	Nice
France	Institut Curie; Oncologie Medicale	Paris
France	CHU Lyon - Centre Hospitalier Lyon Sud	Pierre-Benite (Lyon)
France	Centre Eugene Marquis; Service d'oncologie	Rennes
France	CHU Strasbourg Hôpital Hautepierre	Strasbourg
France	Hopital Foch; Oncologie	Suresnes
France	Institut Gustave Roussy	Villejuif
Germany	Universitätsklinikum Augsburg; II. Med. Klinik	Augsburg
Germany	Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo.	Berlin
Germany	Onkologisches Zentrum - Onkologie Dachau	Dachau
Germany	Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden	Dresden
Germany	Universitätsklinikum Düsseldorf; Klinik für Hämatologie, Onkologie und Klinische Immunologie	Düsseldorf
Germany	Kliniken Essen-Mitte, Evang. Huyssens-Stiftung, Klinik für Internistische Onkologie / Haematologie	Essen
Germany	Universitätsklinikum Frankfurt, UCT; Universitäres Centrum für Tumorerkrankungen	Frankfurt
Germany	Universitätsklinikum Heidelberg;Innere Medizin V, Hämatologie/Onkologie	Heidelberg
Germany	SLK-Kliniken Heilbronn GmbH; Klinik für Innere Medizin III; Schwerpunkt Häma./Onko./Palliativm.	Heilbronn
Germany	Universitätsklinikum Jena, Klinik für Innere Medizin II; Hämatologie und Internistische Onkologie	Jena
Germany	Uni. der Johannes Gutenberg-Universitaet Mainz; III. Medizinische Klinik und Poliklinik	Mainz
Germany	Klinikum Mannheim III. Medizinische Klinik	Mannheim
Germany	Klinikum der LMU München, Campus Großhadern, Krebszentrum München; Comprehensive Cancer Center LMU	München
Germany	Universitätsklinikum Münster, Medizinische Klinik A, Translationale Onkologie	Münster
Germany	RED-Oncology GmbH; Dres.Gerdt Hübner/Clemens Engels (Oldenburg)/Yael Bonnin-Gruber (Eutin)	Oldenburg / Holstein
Greece	Anticancer Hospital Ag Savas; 1St Dept of Internal Medicine	Athens
Greece	IASO General Hospital of Athens	Athens
Greece	Univ General Hosp Heraklion; Medical Oncology	Heraklion
Greece	Uni Hospital of Ioannina; Oncology Dept.	Ioannina
Greece	Theagenio Anticancer Hospital; 3Rd Oncology Clinic	Thessaloniki
Hungary	Budapesti Uzsoki Utcai Kórház; Onkoradiológiai Osztály	Budapest
Hungary	Orszagos Onkologiai Intezet; B Belgyogyaszati Osztaly	Budapest
Hungary	Bács-Kiskun Vármegyei Oktatókórház; Onkoradiológiai Központ	Kecskemét
Ireland	St Vincent'S Uni Hospital; Medical Oncology	Dublin
Ireland	Waterford Regional Hospital; Department Of Medical Oncology	Waterford
Israel	Rabin MC; Davidof Center - Oncology Institute	Petach Tikva
Israel	Chaim Sheba medical center, Oncology division	Ramat Gan
Israel	Tel Aviv Sourasky Medical Ctr; Oncology	Tel Aviv
Italy	Asst Papa Giovanni XXIII; Oncologia Medica	Bergamo	Lombardia
Italy	Policlinico Univ. - A.O. Mater Domini; U.O. Di Oncoematologia	Catanzaro	Calabria
Italy	Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda); Oncologico -Onc.Falck	Milano	Lombardia
Italy	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli	Campania
Italy	IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Prima	Padova	Veneto
Italy	U. O. Oncologia Medica, Ospedale Santa Chiara	Pisa	Basilicata
Italy	Arcispedale Santa Maria Nuova; Oncologia	Reggio Emilia	Emilia-Romagna
Japan	Aichi Cancer Center	Aichi
Japan	National Cancer Center Hospital East	Chiba
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System; Oncology	Seoul
Latvia	Riga East Clinical University Hospital Latvian Oncology Centre	Riga
Mexico	Health Pharma Professional Research	Cdmx	Mexico CITY (federal District)
Mexico	AVIX Investigación Clínica S.C	Monterrey	Nuevo LEON
Netherlands	Erasmus MC	Rotterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Netherlands	Ziekenhuis VieCuri Medisch Centrum	Venlo
Norway	Sørlandet Sykehus Kristiansand	Kristiansand
Norway	Akershus universitetssykehus HF	Lørenskog
Norway	Oslo universitetssykehus HF, Ullevål, Kreftsenteret	Oslo
Peru	Instituto Nacional de Enfermedades Neoplasicas	Lima
Peru	Oncosalud Sac; Oncología	Lima
Poland	Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii	Kraków
Poland	Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie; Oddzial Badan Wczesnych Faz	Warszawa
Portugal	IPO do Porto; Servico de Oncologia Medica	Porto
Romania	Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj Napoca; Oncologie Medicala	Cluj Napoca
Romania	Centrul de Oncologie Sfantul Nectarie	Craiova
Romania	Institutul Regional de Oncologie Iasi; Clinica de Hematologie	Iasi
Romania	Oncocenter Timisoara	Timi?oara
Spain	Hospital Clínic i Provincial; Servicio de Oncología	Barcelona
Spain	Institut Catala d Oncologia Hospital Duran i Reynals	Barcelona
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid
Spain	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga
Spain	Complejo Hospitalario de Navarra; Servicio de Oncologia	Pamplona	Navarra
Spain	Hospital Sant Joan Despi- Moises Broggi; Servicio de Oncologia	Sant Joan Despí	Barcelona
Spain	Hospital Universitario Virgen Macarena; Servicio de Oncologia	Sevilla
Spain	Hospital Universitari i Politecnic La Fe; Oncologia	Valencia
Spain	Complexo Hospitalario de Vigo. Hospital Álvaro Cunqueiro; Servicio de Oncología	Vigo	Pontevedra
Spain	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza
Switzerland	Universitaetsspital Basel; Onkologie	Basel
Switzerland	UniversitätsSpital Zürich; Zentrum für Hämatologie und Onkologie, Klinik für Onkologie	Zürich
Thailand	Faculty of Med. Siriraj Hosp.; Med.-Div. of Med. Oncology	Bangkok
Thailand	Ramathibodi Hospital; Medicine/Oncology; Clinical Research Center	Bangkok
Turkey	Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital; Medical Oncology	Adana
Turkey	Ankara Oncology Hospital; Oncology	Ankara
Turkey	Ankara University Medical Faculty; Medikal Onkoloji	Ankara
Turkey	Akdeniz University Medical Faculty; Medical Oncology Department	Antalya
Turkey	Trakya Universitesi Tip Fakultesi, Medikal Onkoloji Bilim Dali, Balkan Yerleskesi	Edirne
Turkey	Istanbul University Cerrahpa?a-Cerrahpa?a Medical Faculty; Medikal Onkoloji Departmani	Istanbul
Turkey	?zmir Medical Point; Oncology	Kar?iyaka
Turkey	Hacettepe Uni Medical Faculty Hospital; Oncology Dept	Sihhiye/Ankara
United Kingdom	Royal United Hospital; Oncology Department	Bath
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	Western General Hospital; Edinburgh Cancer Center	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Hammersmith Hospital; Garry Weston Centre	London
United Kingdom	University College London Hospitals NHS Foundation Trust - University College Hospital	London
United Kingdom	Christie Hospital NHS Trust	Manchester
United Kingdom	Freeman Hospital	Newcastle upon Tyne
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Torbay Hospital; Oncology Department	Torquay

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Foundation Medicine, Inc.

Countries where clinical trial is conducted

Australia,  Austria,  Brazil,  Bulgaria,  Chile,  Colombia,  Croatia,  Czechia,  Denmark,  Estonia,  Finland,  France,  Germany,  Greece,  Hungary,  Ireland,  Israel,  Italy,  Japan,  Korea, Republic of,  Latvia,  Mexico,  Netherlands,  Norway,  Peru,  Poland,  Portugal,  Romania,  Spain,  Switzerland,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)	This efficacy objective was to evaluate the efficacy of MGT vs platinum chemotherapy in term of PFS in participants with CUP whose best response to 3 cycles of platinum induction chemotherapy was assessed CR, PR, or SD.	From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1).
Secondary	Overall Survival (OS)		From randomization to death from any cause (approx. 4 years)
Secondary	Objective Response Rate (ORR)		Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months)
Secondary	Duration of Response (DOR)		From the first documentation of a complete response (CR) or partial response (PR) to disease progression or death from any cause, whichever occurs first (up to approximately 4 years)
Secondary	Disease Control Rate (DCR)		From randomization to death from any cause, through the end of study (approximately 4 years)