Phase II study of Cemiplimab before and after standard chemoradiotherapy for patients with locally advanced cervical carcinoma. CADILLACC TRIAL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori

Participant type

Patients

Age range

18-64 years

Gender

Female

Therapeutic area

Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Decision date (initial)

2026-02-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The primary objective of CADILACC study is to evaluate the antitumor activity of cemiplimab administered before and after standard CCRT in patients with LACC in terms of objective response rate (ORR), defined as the percentage of the participants who achieve a complete response (CR) or partial response (PR) at the end of mantenance treatment according to RECIST1.1 criteria

Secondary objectives 16

1. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of PFS in all treated patient
2. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of PFS in participants with PD-L1 high expression (PD-L1>=50%)
3. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of OS
4. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of OS in participants with PD-L1 high expression (PD-L1>=50%).
5. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of ORR in participants with PD-L1 high expression ((PD-L1>=50%) after induction phase and maintenance phase.
6. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of DoR in overall
7. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of DoR in participants with PD-L1 high expression (PD-L1>=50%).
8. To evaluate progression-free survival after next-line treatment (progression-free survival 2) following discontinuation of study treatment administration as determined by the investigator according to the local standard of clinical practice
9. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma by assessment of TFST
10. To evaluate incidence of local progression, distant disease progression and secondary malignancy as the first documented progression event
11. To evaluate safety and tolerability of profile of Cemiplimab before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma
12. To assess change from baseline score in global quality of life and physical function using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) global health status/Quality of Life scale and Physical Function subscale in patients with LACC treated with cemiplimab before and after standard chemoradiotherapy
13. To assess change from baseline score in symptom experience using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Symptom Score for Cervical Cancer) the EORTC CX24 symptom specific scale (11 items) in patients with LACC treated with cemiplimab before and after standard chemoradiotherapy
14. To evaluate changes in the Visual Analog Scale and characterize utilities using the European Quality of Life (EQ-5D-5L) instrument
15. To evaluate the antitumor activity of cemiplimab administered before and after standard chemoradiotherapy in patients with locally advanced cervical carcinoma in terms of proportion of patient achiving complete pathological response defined at the end of induction treatment and at the end of maintenance treatment
16. To explore the immune response to “sandwich” immunotherapy integrated with standard CCRT

Conditions and MedDRA coding

locally advanced cervical carcinoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 18

1. Has read and understand the informed consent form and has given written informed consent prior to any study procedures
2. Has provided a tissue sample from a core incisional or excisional biopsy of a tumor lesion
3. Subjects must have adequate hematological function: - Absolute neutrophil count (ANC) ≥1500/μL - Platelets ≥100 000/μL - Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
4. Patient must have adequate renal and hepatic function: -Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the Cockcroft -Gault glomerular filtration rate estimation: (140 − age) ×(weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL); -Serum bilirubin ≤ 1.5 × ULN; with the following exception: Subjects with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled; -AST, ALT, and alkaline phosphatase < 2.5 x ULN, with the following exceptions: Patients with documented liver metastases: AST and ALT < 5 x ULN o Patients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN; -Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
5. Patients must not be pregnant or breastfeeding and agree to use highly effective contraception during the treatment period and for at least 120 days after the last dose of cemiplimab
6. Participants must abstain from breastfeeding during the study intervention period and for at least 120 days after the last dose of cemiplimab or placebo and 180 days following the end of chemoradiotherapy
7. Age > 18 years
8. Life expectancy of at least 3 months
9. Has LACC, FIGO 2018 stage IB3-IVA
10. Has PD-L1 positive (PD-L1 >=1%) tumor
11. Has histologically-confirmed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix
12. Has not previously received any definitive surgical, radiation, or systemic therapy for cervical cancer, including investigational agents, and is immunotherapy-naïve
13. Patient must have ECOG performance status of 0 or 1
14. Subjects must have measurable disease according to RECIST 1.1
15. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation: (140 − age) ×(weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL)
16. Serum bilirubin ≤ 1.5 × ULN; with the following exception: Subjects with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled
17. AST, ALT, and alkaline phosphatase < 2.5 x ULN, with the following exceptions: Patients with documented liver metastases: AST and ALT < 5 x ULN o Patients with documented liver or bone metastases: alkaline phosphatase < 5 x ULN
18. Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Exclusion criteria 22

1. Has histological subtypes other than those allowed per inclusion criterion 2 (eg, sarcoma, small cell carcinoma with neuroendocrine differentiation, non epithelial cancer).
2. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization. NOTE: Participants who have entered the Follow-up Phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
3. Has any contraindication to the use of cisplatin
4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
5. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
6. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). NOTE: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
7. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
8. Has an active infection requiring systemic therapy
9. Has a known history of HIV infection. NOTE: No testing for HIV is required unless mandated by local health authority
10. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority
11. Has had an allogenic tissue/solid organ transplant.
12. Has FIGO 2018 Stage IVB disease. Evidence of metastatic disease per RECIST 1.1 including lymph nodes above the L1 cephalad body or in the inguinal region. NOTE: Participants with inguinal lymph node involvement must be exscluded.
13. Evidence of metastatic disease per RECIST 1.1 including lymph nodes above the L1 cephalad body, in the inguinal region. Participants with inguinal lymph node involvement should be discussed with Sponsor and may potentially be eligible after confirmation of the Sponsor with participant’s disease details
14. Has undergone a previous hysterectomy defined as removal of the entire uterus or will have a hysterectomy as part of their initial cervical cancer therapy
15. Has bilateral severe hydronephrosis, unless at least one side has been stented or resolved by positioning of nephrostomy or considered mild and not clinically significant in the opinion of the investigator
16. Has anatomy or tumor geometry or any other reason or contraindication that cannot be treated with intracavitary brachytherapy or a combination of intracavitary and interstitial brachytherapy
17. Has received a live vaccine within 30 days prior to the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and areallowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
18. Has received treatment with systemic immunostimulatory agents, colony stimulating factors, interferons, interleukins and vaccine combinations within 6 weeks or 5 half-live of the drug, whichever is shorter, prior to Cycle 1, Day 1
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with anagent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
20. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization
21. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results, and in the judgment of the investigator or Sponsor, would make the participant inappropriate for entry into this study.
22. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the objective response rate (ORR), defined as the percentage of the participants who achieve a complete response (CR) or partial response (PR) RECIST 1.1

Secondary endpoints 20

1. Progression-free survival (PFS): is defined as the time from date of enrollment until RECIST 1.1-defined radiological progression or histopathologically confirmed progression as assessed by the Investigator or death due to any cause, whichever occurs earlier
2. Progression-free survival (PFS) in participants with PD-L1 high expression: defined as the time from date of of enrollment until RECIST 1.1-defined radiological progression or histopathologically confirmed progression as assessed by the Investigator or death due to any cause, whichever occurs earlier
3. Progression-free survival rate at 2and 3 years: defined as the proportion of participants that are progression-free survival event-free at 2 and 3 years
4. Progression-free survival at 2 and 3 years in participants with PD-L1 high expression: defined as the proportion of participants that are progression-free survival event-free at 2 and 3 years
5. Overall Survival (OS): defined as time from enrollment until the date of death due to any cause
6. OS in participants with PD-L1 high expression: defined as time from randomization until the date of death due to any cause
7. ORR in participants with PD-L1 high expression: defined as the proportion of participants who have a CR or PR, as determined by Investigator per RECIST 1.1
8. Duration of Response (DoR) in participants with a CR or PR: defined as the time from date of first detection of CR or PR until the date of RECIST 1.1-defined radiological progression or histopathologically confirmed progression
9. DoR in participants with PD-L1 high expression: defined as the DoR in participants with a CR or PR: Time from date of first detection of CR or PR until the date of RECIST 1.1-defined radiological progression or histopathologically confirmed progression
10. PFS2: defined as the time from enrollment to the earliest of the progression event (following the initial Investigator-assessed progression), after first subsequent therapy, or death. The date of second progression will be recorded by the Investigator in the eCRF and defined according to local standard clinical practice
11. TFST: defined as the time from enrollment until the start date of the first subsequent anti-cancer therapy after discontinuation of randomized treatment, or death due to any cause
12. Incidence of Local Progression, and DistaDisease Progression: Number and percentage of participants who develop local progression, distant disease recurrence
13. Percentage of patients with treatment emergent adverse events as defined by CTCAE v.5.0
14. Maximum grade of each adverse event as defined by CTCAE v.5.0 by patient
15. Study treatment discontinuation due to adverse events
16. Description of change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ-C30 Global Score and Physical Function subscale
17. Description of change from baseline in The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (Symptom Score for Cervical Cancer) EORTC QLQ-CX24 symptom specific scale
18. Description of change from baseline Visual Analog Scale and utilities will be assessed using the European Quality of Life EQ-5D-5L
19. Proportion of patient achiving complete pathological response defined at the end of induction phase and at the end of maintenance treatment. Complete pathological responses will be defined as follows: complete disappearance of tumor in the cervix biopsy
20. Description of molecular biomarkers that may be indicative of clinical response/resistance, safety, and/or the mechanism of action of cemiplimab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Clinical trial contact point

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

public relation office

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications