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Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in 1st-line Treatment for Patients With Metastatic Lung Adenocarcinoma (CRYOMUNE)

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ClinicalTrials.gov Identifier: NCT04339218
Recruitment Status : Not yet recruiting
First Posted : April 9, 2020
Last Update Posted : April 21, 2020
Sponsor:
Information provided by (Responsible Party):
Institut Bergonié

Brief Summary:

This study aims to compare the one-year survival benefit of the association of cryoablation-pembrolizumab-pemetrexed-carboplatin versus pembrolizumab-pemetrexed-carboplatin in metastatic lung adenocarcinoma patients.

This is a multicenter, prospective, open-labeled, 2-arm comparative randomized (1:1) phase III trial.

Patients will be randomized with a 1:1 ratio into:

  • Arm A (experimental arm): cryoablation of one visceral lesion or bone metastasis excluding liver and sclerotic bone metastases combined with pembrolizumab and pemetrexed-carboplatin prescribed as per market authorization.
  • Arm B (standard arm): pembrolizumab and pemetrexed-carboplatin prescribed as per market authorization.

Pembrolizumab and pemetrexed-carboplatin will be prescribed and administered at the dose recommended by market authorization.

Cryoablation treatment should be performed within 6 weeks after the first administration of pembrolizumab. No treatment switching permitted.


Condition or disease Intervention/treatment Phase
Lung Adenocarcinoma Cryotherapy Effect Device: Cryoablation Drug: Pembrolizumab Drug: Pemetrexed Drug: Carboplatin Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in First-line Treatment for Patients With Metastatic Lung Adenocarcinoma: A Randomized Phase III Study
Estimated Study Start Date : June 2020
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2025


Arm Intervention/treatment
Experimental: Arm Cryoablation+pembrolizumab-pemetrexed-carboplatin
Cryoablation of one visceral lesion or bone metastasis excluding liver and sclerotic bone metastases combined with pembrolizumab and pemetrexed-carboplatin prescribed as per market authorization.
Device: Cryoablation

Cryoablation will be performed by a specialized radiologist, percutaneously, ie "through the skin". The operation is performed under general anesthesia, under the guidance of the scanner. The images from the scanner make it possible to precisely insert and place a needle at the level of the tumor to be treated. Intense cold will be produced by the needle and will destroy the cancer cells by freezing (temperatures of -40 °C). Freezing is localized to the tumor, the rest of the organ will not suffer from the cold.

The aftermath of the intervention causes only minimal pain and in most cases does not require pain treatment. As the operation is minimally traumatic, the risk of complications is low. Hospitalization is around twenty-four hours and usual or professional activities can be resumed very quickly.


Drug: Pembrolizumab
Pembrolizumab will be prescribed and administered at the dose recommended by market authorization.

Drug: Pemetrexed
Pemetrexed will be prescribed and administered at the dose recommended by market authorization.

Drug: Carboplatin
Carboplatin will be prescribed and administered at the dose recommended by market authorization.

Active Comparator: Arm pembrolizumab-pemetrexed-carboplatin
Combination of Pembrolizumab and pemetrexed-carboplatin prescribed as per market authorization.
Drug: Pembrolizumab
Pembrolizumab will be prescribed and administered at the dose recommended by market authorization.

Drug: Pemetrexed
Pemetrexed will be prescribed and administered at the dose recommended by market authorization.

Drug: Carboplatin
Carboplatin will be prescribed and administered at the dose recommended by market authorization.




Primary Outcome Measures :
  1. 1-year overall survival rate [ Time Frame: 1 year ]
    Overall survival (OS) is defined as the time interval between the date of randomization and the date of death (from any cause). Patients alive will be censored at the date of last follow-up or last patient contact. One-year OS rates will be compared between arms.


Secondary Outcome Measures :
  1. Overall response rate within 6 months as per RECIST v1.1 [ Time Frame: throughout the treatment period, an expected average of 6 months ]
    Overall response rate (ORR) is defined as the rate of patients with complete or partial response (CR, PR) as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.; Overall Response (OR) = CR + PR.

  2. Overall response rate at 6 months as per RECIST v1.1 [ Time Frame: 6 months ]
    Overall response rate (ORR) is defined as the rate of patients with complete or partial response (CR, PR) as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.; Overall Response (OR) = CR + PR.

  3. Overall response rate as per RECIST v1.1 [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Overall response rate (ORR) is defined as the rate of patients with complete or partial response (CR, PR) as per RECIST v1.1. ORR will be assessed across all time points, once all the data for the patient is known. According to RECIST v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.; Overall Response (OR) = CR + PR.

  4. Duration of overall response [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    The duration of overall response (DoR) is defined as the time from documentation of tumour response (Complete or partial responses whichever is first recorded) to disease progression, according to RECIST v1.1. Kaplan-Meier Method will be used to estimate DoR.

  5. Best overall response rate as per RECIST v1.1 [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Best overall response rate (BoR) is defined as rate of patients with the best response across all time points (RECIST v1.1). The best overall response will be determined once all the data for the patient is known.

  6. 2-year overall survival rate [ Time Frame: 2 years ]
    Overall survival (OS) is defined as the time interval between the date of randomization and the date of death (from any cause). 2-year OS rates will be compared between arms.

  7. 1-year progression-free survival rate [ Time Frame: 1 year ]
    Progression-free survival (PFS) is defined as the time interval between the date of randomization and the date of progression (RECIST v1.1) or death (from any cause), whichever occurs first.The analysis of PFS will be based on the censoring process following FDA guidelines. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.1-year PFS rates will be compared between arms.

  8. 2-year progression-free survival rate [ Time Frame: 2 years ]
    Progression-free survival (PFS) is defined as the time interval between the date of randomization and the date of progression (RECIST v1.1) or death (from any cause), whichever occurs first.The analysis of PFS will be based on the censoring process following FDA guidelines. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.2-year PFS rates will be compared between arms.

  9. Mean scores of each dimension of QLQ-C30 from EORTC quality of life group [ Time Frame: at baseline, 3, 6, 9, 12 and 24 months ]
    Health-related quality of life (HRQoL) will be assessed through EORTC QLQ-C30 (Aaronson et al. J Natl Cancer Inst 1993).The QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients. The questionnaire includes one global health status/QoL scale, five functional scales and three symptom scale. Each scale is scored from 0 to 100. A high score on a scale indicate a good outcome for the dimension of QoL.

  10. Time to health-related quality of life score definitive deterioration (targeted dimension of EORTC QLQC30 : global health) [ Time Frame: at baseline, 3, 6, 9, 12 and 24 months ]
    Time until definitive deterioration (TUDD) of HRQoL is defined as the time from the date of randomization to a first deterioration of at least 10 points of HRQoL as compared to the baseline score (Bonnetain et al. Eur J Cancer 2010).

  11. Number of patient receiving a post-progression treatment [ Time Frame: an average of 6 months ]
    Post-progression treatment is defined as the treatment (systemic/local) given after the first progression under cryoablation+pembrolizumab and pemetrexed-carboplatin or pembrolizumab and pemetrexed-carboplatin.

  12. Overall response rate as per iRECIST [ Time Frame: throughout the treatment period, an expected average of 6 months ]
    Overall response rate (ORR) is defined as the rate of patients with immune complete or partial responses (iCR, iPR) as per iRECIST (Seymour et al. 2017). iCR and iPR can be assigned after iUPD (immune unconfirmed progressive disease) has been documented.

  13. Duration of immune overall response [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Duration of i-response (iDoR) is defined as the time from the date of the first response iCR/iPR (whichever is first recorded) to the date of PD (iUPD confirmed as iCPD). iDOR is only defined for subjects who have best overall response of iCR or iPR.

  14. 1-year immune-progression-free survival rate [ Time Frame: 1 year ]
    Immune-progression-free survival (iPFS) is defined as the time interval between the date of randomization and the date of progression (iRECIST) or death (from any cause), whichever occurs first. The event date to be used for calculation of progression-free survival (iPFS) should be the first date at which progression criteria are met (ie, the date of iUPD) provided that iCPD is confirmed at the next assessment. 1-year iPFS rates will be compared between arms.

  15. 2-year immune-progression-free survival rate [ Time Frame: 2 year ]
    Immune-progression-free survival (iPFS) is defined as the time interval between the date of randomization and the date of progression (iRECIST) or death (from any cause), whichever occurs first. The event date to be used for calculation of progression-free survival (iPFS) should be the first date at which progression criteria are met (ie, the date of iUPD) provided that iCPD is confirmed at the next assessment. 2-year iPFS rates will be compared between arms.

  16. Best overall response rate as per iRECIST [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Best overall response rate (iBoR) is defined, according to iRECIST, as the rate of patients with the best timepoint response recorded from the start of the study treatment until the end of treatment, taking into account any requirement for confirmation.

  17. Number of immune-related SAEs (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Serious Adverse events (SAEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  18. Number of immune-related AEs (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Adverse events (AEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  19. Number of chemotherapy-related SAEs (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Serious Adverse events (SAEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  20. Number of chemotherapy-related AEs (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Adverse events (AEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  21. Number of cryoablation-related SAEs (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Serious Adverse events (SAEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  22. Number of cryoablation-related AEs (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Adverse events (AEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  23. Number of SAEs related to study procedures (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Serious Adverse events (SAEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  24. Number of AEs related to study procedures (CTCAE NCI V5) [ Time Frame: throughout the treatment period, an expected average of 1 year ]
    Adverse events (AEs) will be coded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) NCI v5.

  25. Number of hospitalisations in experimental arm only [ Time Frame: within 6 weeks + 30 days after first pembrolizumab administration ]
    counts of hospitalisations within 30 days after the cryoablation will be summarized by treatment strategy.

  26. Percentage of patients that worsen their ECOG score of 1 or more point [ Time Frame: at follow-up visits post randomization (an average of 2 years) ]
    Percentage of patients that worsen their ECOG score of 1 or more point at follow-up visits post randomization will be summarized by treatment strategy.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically or cytologically confirmed non-small lung adenocarcinoma.
  2. Metastatic disease.
  3. Treatment with pembrolizumab in combination with pemetrexed-carboplatin as per market authorization.
  4. At least two target lesions (RECIST1.1), measurable with CT or MRI :

    1. One target lesion that is amenable for accurate repeated measurements,
    2. One target lesion (15-40 mm) that is amenable for cryoablation treatment including lung, kidney, adrenal, soft tissue and lytic bone lesions. Liver and sclerotic bone lesions are not allowed to be treated by cryoablation.
  5. Age ≥ 18.
  6. Performance status ≤ 2.
  7. Women of childbearing potential must have a negative serum pregnancy test prior to registration.
  8. Recovery to grade ≤ 1 from any adverse event derived from previous treatment (excluding alopecia)
  9. Patients with a social security in compliance with the French law (Loi Jardé).
  10. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
  11. Voluntarily signed and dated written informed consents prior to any study specific procedure.

Exclusion Criteria:

  1. Squamous cell tumors and other than adenocarcinoma.
  2. Prior systemic treatment for advanced non-small cell lung cancer (except adjuvant therapy after complete resection).
  3. Current or prior use of immunosuppressive medication including any use of oral glucocorticoids, within 21 days before the first dose of pembrolizumab.
  4. Known contra-indication and/or hypersensitivity to PD1/PD-L1 antagonist and/or cytotoxic therapy.
  5. Known contra-indication to cryoablation.
  6. Abnormal coagulation contraindicating biopsy.
  7. Prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma or incidentally discovered good prognosis prostate cancer (T stage < pT3 and Gleason ≤ 7).
  8. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
  9. Subjects who participated in an investigational drug or device study within 28 days prior to study entry.
  10. Known infection with HIV, hepatitis B, or hepatitis C.
  11. Females who are pregnant or breast-feeding.
  12. Men or women refusing contraception.
  13. Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study.
  14. Previous enrolment in the present study.
  15. Individuals deprived of liberty or placed under legal guardianship.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04339218


Contacts
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Contact: Jean PALUSSIERE, MD 05.56.33.33.47 ext +33 j.palussiere@bordeaux.unicancer.fr
Contact: Simone MATHOULIN-PELISSIER, MD, PhD s.mathoulin@bordeaux.unicancer.fr

Sponsors and Collaborators
Institut Bergonié
Investigators
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Principal Investigator: Jean PALUSSIERE, MD Institut Bergonié
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Responsible Party: Institut Bergonié
ClinicalTrials.gov Identifier: NCT04339218    
Other Study ID Numbers: IB 2019-05
2019-A02477-50 ( Other Identifier: ANSM ID-RCB number )
First Posted: April 9, 2020    Key Record Dates
Last Update Posted: April 21, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut Bergonié:
Lung adenocarcinoma, immunotherapy, cryoablation
Additional relevant MeSH terms:
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Adenocarcinoma
Adenocarcinoma of Lung
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Carboplatin
Pembrolizumab
Pemetrexed
Antineoplastic Agents
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors