Cancer of Unknown Primary SitePhase 2CUPISCONCT03498521
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
A Phase 2 study testing Alectinib, Vismodegib and Ipatasertib in people with Cancer of Unknown Primary Site, run by Hoffmann-La Roche at 125 sites in 33 countries.
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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cancer of Unknown Primary Site
- What is being tested?
- Alectinib, Vismodegib and Ipatasertib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 529 participants
- Where
- 125 sitesin 33 countries
- Study dates
- 10 Jul 2018to 7 Nov 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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
Trial locations and contacts
125 sites in 33 countries.
125 sites in 33 countries
France15 sites
Ico - Paul Papin
Angers, 49000
CHRU Besançon
Besançon, 25030
Institut Bergonie
Bordeaux, 33076
CRLCC-Francois Baclesse
Caen, 14076
Centre Jean Perrin Centre Regional de Lutte Contre Le Cancer D auvergne
Clermont-Ferrand, 63003
Centre Leon Berard
Lyon, 69008
Institut Paoli-Calmettes
Marseille, 13273
Institut régional du Cancer Montpellier
Montpellier, 34298
Centre Antoine Lacassagne
Nice, 06189
Institut Curie
Paris, 75231
CHU Lyon - Centre Hospitalier Lyon Sud
Pierre-Benite (Lyon), 69495
Centre Eugene Marquis
Rennes, 35042
CHU Strasbourg Hpital Hautepierre
Strasbourg, 67098
Hopital Foch
Suresnes, 92151
Institut Gustave Roussy
Villejuif, 94805
Germany10 sites
Universitätsklinikum Augsburg
Augsburg, 86156
Charité-Universitätsm. Berlin
Berlin, 13353
Onkologisches Zentrum - Onkologie Dachau
Dachau, 85221
Universitätsklinikum Frankfurt, UCT
Frankfurt, 60590
SLK-Kliniken Heilbronn GmbH;Klinik für Innere Medizin III
Heilbronn, 74078
Universitätsklinikum Jena, Klinik für Innere Medizin II
Jena, 07740
Klinikum Mannheim III. Medizinische Klinik
Mannheim, 68167
Klinikum der LMU München, Campus Großhadern, Krebszentrum München
München, 81377
Universitätsklinikum Münster, Medizinische Klinik A, Translationale Onkologie
Münster, 48149
RED-Oncology GmbH
Oldenburg / Holstein, 23758
Spain10 sites
Hospital Clínic i Provincial
Barcelona, 08036
Institut Catala d Oncologia Hospital Duran i Reynals
Barcelona, 08908
Hospital Ramon y Cajal
Madrid, 28034
Hospital Clinico Universitario Virgen de la Victoria
Málaga, 29010
Complejo Hospitalario de Navarra
Pamplona, Navarre, 31008
Hospital Sant Joan Despi- Moises Broggi
Sant Joan Despí, Barcelona, 08970
Hospital Universitario Virgen Macarena
Seville, 41009
Hospital Universitari i Politecnic La Fe
Valencia, 46026
Complexo Hospitalario de Vigo. Hospital Álvaro Cunqueiro
Vigo, Pontevedra, 36312
Hospital Universitario Miguel Servet
Zaragoza, 50009
Turkey (Türkiye)8 sites
Baskent University Adana Dr. Turgut Noyan Practice and Research Hospital
Adana, 01250
Ankara University Medical Faculty
Ankara, 06100
Ankara Oncology Hospital
Ankara, 06200
Akdeniz University Medical Faculty
Antalya, 07070
Trakya Universitesi Tip Fakultesi, Medikal Onkoloji Bilim Dali, Balkan Yerleskesi
Edirne, 22030
Istanbul University Cerrahpa?a-Cerrahpa?a Medical Faculty
Istanbul, 34098
?zmir Medical Point
Kar?iyaka, 35575
Hacettepe Uni Medical Faculty Hospital
S?hhiye, Ankara, 06100
United Kingdom8 sites
Royal United Hospital
Bath, BA1 3NG
Velindre Cancer Centre
Cardiff, CF14 2TL
Western General Hospital
Edinburgh, EH4 2XU
Hammersmith Hospital
London, W12 0HS
Christie Hospital NHS Trust
Manchester, M20 4BX
Freeman Hospital
Newcastle upon Tyne, NE7 7DN
Southampton General Hospital
Southampton, SO16 6YD
Torbay Hospital
Torquay, TQ27AA
Italy7 sites
Asst Papa Giovanni XXIII
Bergamo, Lombardy, 24128
Policlinico Univ. - A.O. Mater Domini
Catanzaro, Calabria, 88100
Azienda Socio Sanitaria Territoriale Niguarda (Ospedale Niguarda Ca' Granda)
Milan, Lombardy, 20162
Istituto Nazionale Tumori Fondazione G. Pascale
Naples, Campania, 80131
IRCCS Istituto Oncologico Veneto (IOV)
Padova, Veneto, 35128
U. O. Oncologia Medica, Ospedale Santa Chiara
Pisa, Basilicate, 56100
Arcispedale Santa Maria Nuova
Reggio Emilia, Emilia-Romagna, 42100
Brazil5 sites
Hospital de Cancer de Barretos
Barretos, São Paulo, 14784-400
Hospital Nossa Senhora da Conceicao
Porto Alegre, Rio Grande do Sul, 91350-200
Instituto Nacional de Cancer - INCa
Rio de Janeiro, 20560-120
Hospital Sao Rafael - HSR
Salvador, Estado de Bahia, 41253-190
Instituto do Cancer do Estado de Sao Paulo - ICESP
São Paulo, São Paulo, 01246-000
Greece5 sites
Anticancer Hospital Ag Savas
Athens, 115 22
IASO General Hospital of Athens
Athens, 155 62
Univ General Hosp Heraklion
Heraklion, 711 10
Uni Hospital of Ioannina
Ioannina, 455 00
Theagenio Anticancer Hospital
Thessaloniki, 540 07
Romania4 sites
Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj Napoca
Cluj-Napoca, 400015
Centrul de Oncologie Sfantul Nectarie
Craiova, 200347
Institutul Regional de Oncologie Iasi
Iași, 700483
Oncocenter Timisoara
Timi?oara, 300166
South Korea4 sites
Seoul National University Hospital
Seoul, 03080
Asan Medical Center
Seoul, 05505
Samsung Medical Center
Seoul, 06351
Severance Hospital, Yonsei University Health System
Seoul, 120-752
Australia3 sites
Blacktown Hospital
Blacktown, New South Wales, NSW 2148
Icon Cancer Foundation
South Brisbane, Queensland, 4101
GenesisCare North Shore
St Leonards, New South Wales, 2065
Austria3 sites
Lkh-Univ. Klinikum Graz
Graz, 8036
Lkh Salzburg - Univ. Klinikum Salzburg
Salzburg, 5020
Medizinische Universität Wien
Vienna, 1090
Colombia3 sites
Clinica del Country
Bogotá, 11001
Inst. Nacional de Cancerologia
Bogotá
Oncomedica S.A.
Montería, 230002
Czechia3 sites
Masarykuv onkologicky ustav
Brno, 656 53
Fakultni nemocnice Olomouc
Olomouc, 779 00
Fakultni Poliklinika Vseobecne Fakultni Niemocnice
Prague, 128 08
Hungary3 sites
Orszagos Onkologiai Intezet
Budapest, 1122
Budapesti Uzsoki Utcai Kórház
Budapest, 1145
Bács-Kiskun Vármegyei Oktatókórház
Kecskemét, 6000
Israel3 sites
Rabin MC
Petah Tikva, 4941492
Chaim Sheba medical center, Oncology division
Ramat Gan, 5262000
Tel Aviv Sourasky Medical Ctr
Tel Aviv, 6423906
Japan3 sites
Aichi Cancer Center
Aichi, 464-8681
National Cancer Center Hospital East
Chiba, 277-8577
National Hospital Organization Kyushu Cancer Center
Fukuoka, 811-1395
Netherlands3 sites
Erasmus MC
Rotterdam, 3015 GD
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX
Ziekenhuis VieCuri Medisch Centrum
Venlo, 5912 BL
Norway3 sites
Sørlandet Sykehus Kristiansand
Kristiansand, 4604
Akershus universitetssykehus HF
Lørenskog, 1478
Oslo universitetssykehus HF, Ullevål, Kreftsenteret
Oslo, 0450
Chile2 sites
Bradford Hill Centro de Investigaciones Clinicas
Recoleta, 8420383
James Lind Centro de Investigación Del Cáncer
Temuco, 4800827
Finland2 sites
Helsinki University Central Hospital
Helsinki, 00250
Tampere University Hospital
Tampere, 33520
Ireland2 sites
St Vincent'S Uni Hospital
Dublin, D04 T6F4
Waterford Regional Hospital
Waterford, X91 ER8E
Mexico2 sites
Health Pharma Professional Research
CD Mexico, Mexico CITY (federal District), 03810
AVIX Investigación Clínica S.C
Monterrey, Nuevo León, 64710
Peru2 sites
Instituto Nacional de Enfermedades Neoplasicas
Lima, 15038
Oncosalud Sac
Lima, 41
Switzerland2 sites
Universitaetsspital Basel
Basel, 4031
UniversitätsSpital Zürich
Zurich, 8091
Thailand2 sites
Ramathibodi Hospital;Medicine/Oncology
Bangkok, 10400
Faculty of Med. Siriraj Hosp.
Bangkok, 10700
Estonia1 site
North Estonia Medical Centre, Oncology and hematology Clinic
Tallinn, 13419
Latvia1 site
Riga East Clinical University Hospital Latvian Oncology Centre
Riga, LV-1079
Poland1 site
Szpital Uniwersytecki w Krakowie, Oddzia? Kliniczny Kliniki Onkologii
Krakow, 30-688
About this study
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
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.
- Conditions
- Cancer of Unknown Primary Site
- Medical subject headings
- Neoplasms, Unknown Primary
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AlectinibDrug
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).
VismodegibDrug
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).
IpatasertibDrug
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).
OlaparibDrug
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).
ErlotinibDrug
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)
BevacizumabDrug
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)
VemurafenibDrug
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)
CobimetinibDrug
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)Drug
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)
PertuzumabDrug
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)
AtezolizumabDrug
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).
CarboplatinDrug
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.
PaclitaxelDrug
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
CisplatinDrug
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.
GemcitabineDrug
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.
EntrectinibDrug
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).
IvosidenibDrug
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.
PemigatinibDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Molecularly-Guided Therapy | Experimental | Participants will be assigned to molecularly-guided therapy based on genomic profile. Receives: Drug: Alectinib; Drug: Vismodegib; Drug: Ipatasertib; Drug: Olaparib; Drug: Erlotinib; Drug: Bevacizumab; Drug: Vemurafenib; Drug: Cobimetinib; Drug: Trastuzumab Subcutaneous (SC); Drug: Pertuzumab; Drug: Atezolizumab; Drug: Paclitaxel; Drug: Entrectinib; Drug: Ivosidenib; Drug: Pemigatinib |
| Platinum-Based Chemotherapy | Active comparator | Participants will receive platinum-based chemotherapy (Carboplatin or Cisplatin in combination with Gemcitabine or Paclitaxel). Receives: Drug: Trastuzumab Subcutaneous (SC); Drug: Pertuzumab; Drug: Carboplatin; Drug: Paclitaxel; Drug: Cisplatin; Drug: Gemcitabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (4)
Overall Survival (OS)
Measured: From randomization to death from any cause (approx. 4 years)
Objective Response Rate (ORR)
Measured: Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months)
Duration of Response (DOR)
Measured: 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)
Disease Control Rate (DCR)
Measured: From randomization to death from any cause, through the end of study (approximately 4 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2018
- Study start10 Jul 2018
- Primary completion14 Feb 2023
- Study completion7 Nov 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Cancer of Unknown Primary SiteStudies of the same condition, open and under way.
- More trials run by Hoffmann-La RocheThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 529 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hoffmann-La Roche
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Foundation Medicine
- Responsible party
- Sponsor
- Investigators
- Clinical Trials, Study director, Hoffmann-La Roche
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03498521
- Sponsor's protocol ID
- MX39795
- Other IDs
- 2017-003040-20, 2017
- Acronym
- CUPISCO
- Status last verified
- Nov 2025
- First submitted
- 5 Apr 2018
- Last updated
- 19 Nov 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data\_sharing
Publications
Kramer A, Bochtler T, Pauli C, Shiu KK, Cook N, Janoski de Menezes J, Pazo-Cid RA, Losa F, Robbrecht DGJ, Tomasek J, Arslan C, Ozguroglu M, Arni P, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Duran-Pacheco G, Ma N, Scarato J, Ross JS, Moch H, Mileshkin L. Molecularly Guided Therapy Versus Continued Chemotherapy in Unfavorable Cancer of Unknown Primary: Updated Efficacy and Safety From the Randomized, Phase II CUPISCO Study. J Clin Oncol. 2026 Sep 3:JCO2502974. doi: 10.1200/JCO-25-02974. Online ahead of print.
PubMed 42691436Kramer A, Bochtler T, Pauli C, Shiu KK, Cook N, de Menezes JJ, Pazo-Cid RA, Losa F, Robbrecht DG, Tomasek J, Arslan C, Ozguroglu M, Stahl M, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Duran-Pacheco G, Michaud C, Scarato J, Thomas M, Ross JS, Moch H, Mileshkin L. Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study. Lancet. 2024 Aug 10;404(10452):527-539. doi: 10.1016/S0140-6736(24)00814-6. Epub 2024 Jul 31.
PubMed 39096924
Study at a glance
From the registry record, last updated by the sponsor on 19 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03498521
- Acronym / sponsor ID
- CUPISCO / MX39795
- Conditions
- Cancer of Unknown Primary Site
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 529 participants (actual)
- Lead sponsor
- Hoffmann-La RocheIndustry (pharma, biotech, devices)
- Collaborators
- Foundation Medicine
- Study start
- 10 Jul 2018 (actual)
- Primary completion
- 14 Feb 2023 (actual)
- Study completion
- 7 Nov 2024 (actual)
- First posted
- 13 Apr 2018 (actual)
- Results
- Posted 14 Jun 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Molecularly-Guided Therapy | Experimental | Drug: Alectinib, Drug: Vismodegib, Drug: Ipatasertib, Drug: Olaparib, Drug: Erlotinib, Drug: Bevacizumab, Drug: Vemurafenib, Drug: Cobimetinib, Drug: Trastuzumab Subcutaneous (SC), Drug: Pertuzumab, Drug: Atezolizumab, Drug: Paclitaxel, Drug: Entrectinib, Drug: Ivosidenib, Drug: PemigatinibParticipants will be assigned to molecularly-guided therapy based on genomic profile. |
| Platinum-Based Chemotherapy | Active comparator | Drug: Trastuzumab Subcutaneous (SC), Drug: Pertuzumab, Drug: Carboplatin, Drug: Paclitaxel, Drug: Cisplatin, Drug: GemcitabineParticipants will receive platinum-based chemotherapy (Carboplatin or Cisplatin in combination with Gemcitabine or Paclitaxel). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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)
Key exclusion criteria (9 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AlectinibAlectinib 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). | Drug | Molecularly-Guided Therapy |
| VismodegibVismodegib 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). | Drug | Molecularly-Guided Therapy |
| IpatasertibIpatasertib 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). | Drug | Molecularly-Guided Therapy |
| OlaparibOlaparib 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). | Drug | Molecularly-Guided Therapy |
| ErlotinibErlotinib 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) | Drug | Molecularly-Guided Therapy |
| BevacizumabBevacizumab 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) | Drug | Molecularly-Guided Therapy |
| VemurafenibVemurafenib 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) | Drug | Molecularly-Guided Therapy |
| CobimetinibCobimetinib 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) | Drug | Molecularly-Guided Therapy |
| 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) | Drug | Molecularly-Guided Therapy, Platinum-Based Chemotherapy |
| PertuzumabPertuzumab 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) | Drug | Molecularly-Guided Therapy, Platinum-Based Chemotherapy |
| AtezolizumabAtezolizumab 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). | Drug | Molecularly-Guided Therapy |
| CarboplatinCarboplatin 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. | Drug | Platinum-Based Chemotherapy |
| PaclitaxelPaclitaxel 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 | Drug | Molecularly-Guided Therapy, Platinum-Based Chemotherapy |
| CisplatinCisplatin 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. | Drug | Platinum-Based Chemotherapy |
| GemcitabineGemcitabine 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. | Drug | Platinum-Based Chemotherapy |
| EntrectinibEntrectinib 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). | Drug | Molecularly-Guided Therapy |
| IvosidenibIvosidenib 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. | Drug | Molecularly-Guided Therapy |
| PemigatinibPemigatinib 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. | Drug | Molecularly-Guided Therapy |
Primary outcome
Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)
Time frame: 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).
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.
4 secondary outcomes
Overall Survival (OS)
Time frame: From randomization to death from any cause (approx. 4 years)
Objective Response Rate (ORR)
Time frame: Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months)
Duration of Response (DOR)
Time frame: 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)
Disease Control Rate (DCR)
Time frame: From randomization to death from any cause, through the end of study (approximately 4 years)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Nov 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42691436Kramer A, Bochtler T, Pauli C, Shiu KK, Cook N, Janoski de Menezes J, Pazo-Cid RA, Losa F, Robbrecht DGJ, Tomasek J, Arslan C, Ozguroglu M, Arni P, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Duran-Pacheco G, Ma N, Scarato J, Ross JS, Moch H, Mileshkin L. Molecularly Guided Therapy Versus Continued Chemotherapy in Unfavorable Cancer of Unknown Primary: Updated Efficacy and Safety From the Randomized, Phase II CUPISCO Study. J Clin Oncol. 2026 Sep 3:JCO2502974. doi: 10.1200/JCO-25-02974. Online ahead of print.
- Derived from this study: PubMed 39096924Kramer A, Bochtler T, Pauli C, Shiu KK, Cook N, de Menezes JJ, Pazo-Cid RA, Losa F, Robbrecht DG, Tomasek J, Arslan C, Ozguroglu M, Stahl M, Bigot F, Kim SY, Naito Y, Italiano A, Chalabi N, Duran-Pacheco G, Michaud C, Scarato J, Thomas M, Ross JS, Moch H, Mileshkin L. Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study. Lancet. 2024 Aug 10;404(10452):527-539. doi: 10.1016/S0140-6736(24)00814-6. Epub 2024 Jul 31.
- Individual participant dataSharing planned: Yes. For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Trials study director
Hoffmann-La Roche
125 sites in 33 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alectinib, Vismodegib and Ipatasertib in people with Cancer of Unknown Primary Site, run by Hoffmann-La Roche at 125 sites in 33 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 125 sites in France, Germany, Spain, Turkey (Türkiye), United Kingdom and 28 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 14 Jun 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) (time frame: 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).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03498521, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Nov 2025.