Trial of Pembrolizumab in Cancer of Unknown Primary

NCT03752333 | Completed Phase 2 Results DMC

• 1 other identifier: C/37/2017
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 3

Brief Summary

Abbreviated Title : CUPem Clinical Indication : A Phase II, Two-Stage, Trial of Pembrolizumab in Cancer of unknown primary Trial Type : Single Arm, non-randomised; Two-stage; Hypothesis generating Type of control : None Route of administration : IV Trial Blinding : N/A Treatment Groups :Two cohorts: (i) First Cohort: One or more lines of prior therapy (ii) Second Cohort: First Line untreated CUP patients Number of trial subjects : i) First Cohort: 20 ii) Second Cohort: 57 Eligibility Criteria : The Eligibility Criteria are the same as used in the A trial of chemotherapy for cancer of unknown primary (CUP-ONE) trial in the United Kingdom (UK), please see below.

• Histologically confirmation of a diagnosis of CUP, with imaging and all diagnostic investigations confirmed as CUP within a CUP Multidisciplinary Team (MDT).
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Patients must have disease that is not amenable to potentially curative options such as resection or radical radiotherapy
• If patient's disease presentation precludes tumour biopsy (inaccessible or biopsy thought not to be in the patient's best interest), the patient is not study eligible. Estimated recruitment period : 2 years Estimated duration of trial : 3.9 years including set up, recruitment, follow up and close down. Duration of Participation : Cohort 1 = 6-8 months; Cohort 2 = 8-18 months Estimated average length of treatment per patient =6 months

Conditions

Cancer of Unknown Primary Site

Keywords

Carcinoma, Oncology, Cancer biology

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR) by RECIST Criteria v1.1 in the Second-line & First-line Setting.

  The Response Evaluation Criteria in Solid Tumours (RECIST) criteria v1.1. classifies response based on the assessment of target and non-target lesions on CT scans as: Complete Response (CR): requires all of: * disappearance of all target and non-target lesions * pathological lymph nodes must have reduced to \<10 mm in short axis * no new lesions Partial Response (PR): requires all of: * at least 30% decrease in sum of diameters (SOD) of target lesions compared to baseline sum diameters * non-progressive disease of non-target lesions * no new lesions Progressive Disease (PD): either one of: * any new lesions * at least 20% relative and 5 mm absolute increase of SOD of target lesions compared to smallest SOD ever recorded for the patient Stable Disease (SD): not meeting criteria for PD or PR.

  From the start of the study treatment until the end of treatment, an average of 6-8 months.

Secondary Outcomes (2)

• Incidence Proportion of Adverse Events up to 8 Weeks After the Last Dose of Pembrolizumab in the Second Line Setting

  6-8 months, based on average length of treatment per patient

• Incidence of Adverse Events up to 8 Weeks After the Last Dose of Pembrolizumab in Performance Status 2 (PS2) Patients in Any Setting

  6-8 months (based on average length of treatment per patient)

Other Outcomes (1)

• Identification of Potential Genomic Biomarkers Predictive of Immune Response to Pembrolizumab

  12 months (post study completion)

Study Arms (1)

Pembrolizumab

EXPERIMENTAL

All trial treatments will be administered on an outpatient basis. Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).

Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Pembrolizumab has high affinity and potent receptor blocking activity for PD-1, based on preclinical in vitro data. Pembrolizumab has an acceptable preclinical and clinical safety profile and is in clinical development as an IV immunotherapy for advanced malignancies. The PD-1 pathway represents a major immune control switch, which may be engaged by tumour cells to overcome active T-cell immune surveillance. Pembrolizumab is a potent and highly selective humanized mAb of the Immunoglobulin (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and ultimately immune rejection.

Also known as: Keytruda

Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be willing and able to provide written informed consent/assent for the trial.
• Be 18 years of age on day of signing informed consent.
• Have measurable disease based on RECIST 1.1
• Be willing to provide consent for archival tumour (in the form of formalin fixed paraffin embedded (FFPE) block) or fresh tumour material (if judged technically feasible by radiologist is mandatory for diagnosis and biomarker analysis.
• Have a performance status of 0-2 on the ECOG Performance Scale.
• Cohort 1 - have had at least one prior line / regimen of chemotherapy appropriate for CUP (at least 2 cycles), have not had a RECIST response to first-line chemotherapy, or are progressing after an initial response, or are treatment intolerant to first-line chemotherapy, due to unacceptable toxicity.
• Cohort 2 - be chemo-naive for CUP\*
• \*Previous chemotherapy for other cancers is allowed
• Adequate organ and bone marrow function (all screening tests should be performed within 10 days of treatment initiation):
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Haemoglobin ≥ 9 g/dL (≥90 g/L) without transfusion or Erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or Creatinine clearance\* ≥ 60 mL/min for patients with creatinine levels \> 1.5 x ULN
• \* Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels \>1.5 ULN

You may not qualify if:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of active Bacillus Tuberculosis (TB)
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has active autoimmune disease that has required 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.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

Sponsors & Collaborators

• Imperial College London: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (3)

Hammersmith Hospital - Imperial College Healthcare NHS Trust

Hammersmith, London, W12 0HS, United Kingdom

Location

Gastrointestinal Units, The Royal Marsden NHS Foundation Trust (Sutton and Chelsea)

Sutton, Surrey, United Kingdom

Location

Guy's Cancer Centre, Guy's and St Thomas' NHS Foundation Trust

London, United Kingdom

Location

Related Publications (4)

• Hemminki K, Bevier M, Hemminki A, Sundquist J. Survival in cancer of unknown primary site: population-based analysis by site and histology. Ann Oncol. 2012 Jul;23(7):1854-63. doi: 10.1093/annonc/mdr536. Epub 2011 Nov 24.

  PMID: 22115926 BACKGROUND

• Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021 Mar 26;371(6536):eabc4552. doi: 10.1126/science.abc4552.

  PMID: 33766858 BACKGROUND

• Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G, Gigi E, Meltser A, Douglas GM, Kamer I, Gopalakrishnan V, Dadosh T, Levin-Zaidman S, Avnet S, Atlan T, Cooper ZA, Arora R, Cogdill AP, Khan MAW, Ologun G, Bussi Y, Weinberger A, Lotan-Pompan M, Golani O, Perry G, Rokah M, Bahar-Shany K, Rozeman EA, Blank CU, Ronai A, Shaoul R, Amit A, Dorfman T, Kremer R, Cohen ZR, Harnof S, Siegal T, Yehuda-Shnaidman E, Gal-Yam EN, Shapira H, Baldini N, Langille MGI, Ben-Nun A, Kaufman B, Nissan A, Golan T, Dadiani M, Levanon K, Bar J, Yust-Katz S, Barshack I, Peeper DS, Raz DJ, Segal E, Wargo JA, Sandbank J, Shental N, Straussman R. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020 May 29;368(6494):973-980. doi: 10.1126/science.aay9189.

  PMID: 32467386 BACKGROUND

• Wasan H, Paul J, Nicolson MC, Evans TRJ, McMahon L, Morris A, McCartney E, Bridgewater C, Bowtell D, Erlander M, Oien KA. Clinical outcomes from the UK CUP-ONE Study: A Multi-centre trial to assess the efficacy of Epirubicin, Cisplatin and Capecitabine (ECX) in carcinomas of unknown primary (CUP) with prospective validation of molecular classifiers. Annals of Oncology 25 (Supplement 4): iv394-iv405, 2014. doi:10.1093/annonc/mdu345.8

  RESULT

Related Links

• Outcomes of CUPem: A prospective phase II multicentre clinical trial of pembrolizumab in patients with pre-treated cancer of unknown primary

MeSH Terms

Conditions

Neoplasms, Unknown Primary; Carcinoma; Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasm Metastasis; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Limitations and Caveats

1. Dissolution of the NCRI CUP Working Group affect sample acquisitions and engagement around NCRI CUP working infrastructure. 2. External factors in addition to the dissolution of the NCRI CUP working group and post-COVID research infrastructure challenges results in low sample size and limited number of negative controls (compared to 350 in previous ICI research) that made it difficult to filter out bacterial taxa associated with contamination, adversely affecting the exploratory analysis.

Results Point of Contact

• Title: Professor Harpreet Wasan (Chief Investigator)
• Organization: Imperial College London

h.wasan@imperial.ac.uk; cupem@imperial.ac.uk

+44(0) 20 8383 3089

Study Officials

• Harpreet Wasan, MBBS, FRCP

  Imperial College London

  PRINCIPAL INVESTIGATOR

• Sheela Rao, MBBS, FRCP

  The Royal Marsden Hospitals, Sutton and Chelsea

  PRINCIPAL INVESTIGATOR

• Sarah Ngan, MBBS, FRCP

  Guy's and St Thomas' NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2018
• First Posted: November 26, 2018
• Study Start: February 22, 2019
• Primary Completion: March 31, 2025
• Study Completion: March 31, 2025
• Last Updated: May 4, 2026
• Results First Posted: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)