The CUPISCO study – options for innovative news clinical trials that explore how to improve outcomes for patients with CUP syndrome.

CUPISCO Study

In this section you will be introduced to the CUPISCO study. This clinical trial aims to determine the efficacy and safety of targeted therapies and cancer immunotherapies for patients with a subset of CUP syndrome. The selection of therapies is based on results from comprehensive genomic profiling.

The Cupisco Study

The study title

The phase II CUPISCO study (NCT03498521) compares the efficacy and safety of targeted therapy or immunotherapy guided by CGP vs platinum-based standard chemotherapy in patients with poor prognosis CUP who have received 3 cycles of platinum doublet induction therapy.

CUPISCO – make the unknown known.

Clinicaltrials.gov identifier: NCT03498521. Available at clinicaltrials.gov/ct2/show/NCT03498521.

Background Information

Approximately 85% of CUP cases are assumed to have a clinically relevant genomic alteration and may respond to molecularly-guided therapy.1 The phase II CUPISCO study is evaluating the efficacy and safety of molecularly-guided therapy after CGP in CUP patients with poor prognosis.2

What are the survival rates for CUP patients with poor prognosis?

The survival rates for patients with poor prognosis are low:3

  • 1 year: 38%
  • 5 years: 10%
  • 10 years: 8%
Survival rates for CUP patients with poor prognosis: Minnie Pearl Cancer Research Network – CUP patients treated in phase II studies Survival (%) (N = 396); 1 year 38%; 5 years 10%; 10 years: 8%.

What is the potential of identifying genomic alterations in CUP?

Most CUP samples exhibit genomic alterations. For example, as described in a publication by Ross JS et al. samples from 200 CUP cases were analysed with CGP (Foundation Medicine tissue biopsy assay) to determine whether it is possible to identify genomic alterations that can serve as a basis for targeted therapy.1 Of the 200 CUP cases, 96% exhibited at least one genomic alteration, with one or more clinically relevant genomic alterations identified in 85% of these cases (169 of 200).

The potential of identifying genomic alterations in CUP? 96% of 200 profiled CUP cases harboured at least one genomic alteration – 85% of those cases had ≥ 1 clinically relevant genomic alteration(s) identified (169 of 200).

WHAT ARE THE MUTUAL BENEFITS FOR CGP AND CUP?

CUP may be a potential model disease for clinical utility of CGP in a pan-tumour fashion, independent from the site of tumour origin. Simultaneously, CGP can direct new treatment options in patients with CUP.

CUP is associated with a high unmet need which could be addressed with genomic profiling; CUP is a potential model to test clinical utility of genomic profiling in a histology-independent setting; CUPISCO is a novel clinical trial aiming to show benefit associated with using genomic profiling to define treatment arms and provide molecularly-guided therapies vs chemotherapy in patients with CUP.

1. Ross JS et al. JAMA Oncol 2015; 1: 40–9.
2. Clinicaltrials.gov identifier: NCT03498521. Available at: clinicaltrials.gov/ct2/show/NCT03498521.
3. Greco FA and Hainsworth JD (2011) Cancer of unknown primary site, DeVita VT Jr., Hellman S, Rosenberg SA (eds) Cancer: Principles and Practice of Oncology (9th ed) Philadelphia, PA, JB Lippincott: 2033–51.

Rationale for a study in CUP patients

What is the rationale for the CUPISCO study?

CGP could offer patients with poor prognosis CUP new options for treatment since it permits the identification of potentially clinically relevant alterations in CUP.1-6 The main objective of the study is to determine the efficacy and safety of molecularly-guided therapies based on CGP vs a standard chemotherapy regimen.7

Rationale for a study in CUP patients – context: comprehensive genomic profiling can identify clinically relevant genomic alterations and can direct new treatment options in patients with CUP. – Need: new clinical trials are needed to explore the efficacy and safety of molecularly-guided therapy vs standard chemotherapy across a large cohort of patients with CUP.

1. Frampton GM et al. Nat biotechnol 2013; 31: 1023–31.
2. He J et al. Blood 2016; 127: 3004–14.
3. Gagan J and van Allen EM. Genome Med 2015; 7: 80.
4. Rozenblum AB et al. J Thorac Oncol 2017; 12: 258–68.
5. Suh JH et al. Oncologist 2016; 21: 684–91.
6. Ettinger DS et al. NCCN Guidelines version 2.2019.
7. Clinicaltrials.gov identifier: NCT03498521. Available at clinicaltrials.gov/ct2/show/NCT03498521.
8. Ross JS et al. JAMA Oncol 2015; 1: 40–9.
9. Kato S et al. Cancer Res 2017; 77: 4238–46.
10. Krämer A et al. J Clin Oncol 2018; 36: 15 (suppl e24162).

CUPISCO study design

The CUPISCO study will recruit a total of 790 patients. The planned study duration will be approximately 48 months.1

Tumour profiles of CUP patients are determined from tissue and blood samples using the Foundation Medicine tissue biopsy assay and Foundation Medicine liquid biopsy assay, respectively.2

After 3 cycles of platinum doublet (carboplatin/paclitaxel, cisplatin/gemcitabine or carboplatin/gemcitabine) induction therapy, the responder patients are randomised:1

  • Experimental arm: targeted therapy tailored to the molecular profile
  • Standard arm: continuation of systemic chemotherapy

The non-responder patients go directly to molecularly-guided therapy (according to their genomic profile).

 

What is the CUPISCO study design and what are the study endpoints?

The study endpoints are:

  • Primary endpoint: progression-free survival (PFS)
  • Secondary endpoints:
    • Overall survival (OS)
    • Overall response rate (ORR)
    • Duration of clinical benefit (DCB)
    • Adverse events (AEs)1

1. Clinicaltrials.gov identifier: NCT03498521. Available at: clinicaltrials.gov/ct2/show/NCT03498521.
2. Foundation Medicine, Inc. 2018. Available at: www.foundationmedicine.com (last accessed March 2019).

Key CUPISCO Study Criteria

What are the criteria for inclusion?

On the right-hand side you can see a selection of key inclusion criteria for the CUPISCO study.

Key CUPISCO study criteria – inclusion: age > 18 years; no prior lines of therapy; eligible for platinum-based doublet chemotherapy; ECOG performance status of 0 or 1; poor-risk CUP, for which a likely tissue of origin cannot be posited; sufficient tumour tissue sample for: diagnosis of CUP at the study site’s local laboratory, and Foundation Medicine tissue based comprehensive genomic profiling at a central reference pathology laboratory (whenever possible); adenocarcinoma, undifferentiated adenocarcinoma, undifferentiated carcinoma; central pathology confirmation of compatibility with CUP diagnosis; histologically confirmed metastatic or advanced unresectable CUP; at least one lesion that is measurable (RECIST v1.1); ECOG: Eastern Cooperative Oncology Group; RECIST: response evaluation criteria in solid tumours.

Why might a patient be excluded?

On the right-hand side you can see a selection of key exclusion criteria for the CUPISCO study.

Key CUPISCO study criteria – exclusion: non-epithelial CUP neoplasm, squamous cell carcinomas; immunohistochemistry profile that provides a definitive clinical suspicion of a primary cancer with a specific treatment; history of malignancy other than CUP within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5 year overall survival rate of 90%); favourable prognostic subsets; within 4 weeks of first study treatment dose: major surgery, radiotherapy; central nervous system (CNS) metastases, spinal cord metastases; leptomeningeal disease.

Clinicaltrials.gov identifier: NCT03498521. Available at: clinicaltrials.gov/ct2/show/NCT03498521.

Central eligibility review process

How is trial eligibility decided?

The eligibility review process allows for patient enrolment in the CUPISCO study according to ESMO clinical guidelines.1

CUPISCO – central eligibility review process – local CUP diagnosis: during pre-screening period, site to confirm CUP diagnosis based on pathology as well as the clinical point-of-view based on: ESMO guidelines 2015 algorithm; protocol eligibility criteria; data entry: sites enter all eligibility data in eCRF; ERT review: CUP criteria reviewed according to: ESMO guidelines 2015 algorithm; protocol eligibility criteria; decision processing: Sponsor Medical Monitors enter in IxRS: CUP diagnosis result AND eligibility decision. – eCRF: electronic case report form; ERT: eligibility review team; ESMO: European Society for Medical Oncology; IxRS: interactive voice/web response system.

1. Fizazi K et al. Ann Oncol 2015; 26 (suppl 5): v133–8.

Foundation Medicine’s curated CGP report

What is provided in the CGP report from Foundation Medicine?

CGP results will be provided in a clear, in-depth report that offers information, including tumour mutational burden, microsatellite instability and genomic alterations. Treatment options based on approved therapies or clinical trials are also provided.

Foundation Medicine Report

Sample report as used in CUPISCO study.

THE MOLECULAR TUMOUR BOARD

What is the role of the molecular tumour board (MTB)?

The MTB consists of medical experts in CUP oncology and pathology. It aims to provide independent guidance to the investigator regarding the choice of molecularly-guided therapy based on the CGP report.

CUPISCO – THE MOLECULAR TUMOUR BOARD – advise on the interpretation of the CGP report and the recommended treatment options; – reference oncologists; reference pathologists; investigator and optionally local pathologist; – at least one reference oncologist and one reference pathologist will attend each MTB meeting with the investigator – CGP: comprehensive genomic profiling; MTB: molecular tumour board.

Roche data on file, Molecular Tumor Board Charter MX39795 v9.

CUPISCO study sites

What is the reach of the CUPISCO study?

CUPISCO is a global study with 124 sites planned to participate in 32 countries.

CUPISCO study sites: Finland, Norway, Denmark, Netherlands, UK, Ireland, Spain, Portugal, Brazil,  Peru, Mexico, Italy, Greece, Bulgaria, Korea, Australia,  Estonia, Latvia, Poland, Czechia, Germany, Austria, Switzerland, Hungary, Romania, France, Croatia, Thailand, Turkey, Kazakhstan, Colombia, Israel.