Clinical trial NCT04339218: Cryoablation in Combination (or Not) With Pembrolizumab and Pemetrexed-carboplatin in 1st-line Treatment for Patients With Metastatic Lung Adenocarcinoma
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Lung Adenocarcinoma
Cryotherapy Effect
Keywords: Lung adenocarcinoma, immunotherapy, cryoablation
Lead sponsor: Institut Bergonié
Sponsor class: OTHER
First posted: 2020-04-09
Enrollment: 214
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: Upon signature of the informed consent and verification of the screening results, eligible participants will be randomized between two therapeutic strategies:

* Arm A (experimental arm): cryoablation of 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 treatment should begin no later than 7 days after randomization. The cryoablation treatment should be performed within 6 weeks after the first administration of pembrolizumab.

RECIST v1.1 tumour assessment:Tumour response will be defined and assessed as per the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

* A comprehensive workup will be performed at baseline and every 9 weeks.
* The same method will be used to evaluate each identified lesion both at baseline and throughout the study.
* Treatment will be administered as long as no disease progression or unacceptable toxicity is found, or as long as no other reasons for treatment discontinuation are met.
* Assessment of efficacy will be essentially based on a set of measurable lesions identified at baseline as target lesions and followed until disease progression and following the RECIST v1.1 criteria.
* Confirmation of response at least 4 weeks later is not required in this randomized study where response is not the primary endpoint.

SAFETY :Patients will be evaluable for safety if they have received at least one treatment administration. Safety profile will be continuously followed during treatment up to 90 days after the last immunotherapy treatment administration or until the start of a new antitumor therapy or until 12 months of treatment, whichever occurs first.

STUDY PROCEDURES :

Blood sample will be collected at baseline (Day 1: before treatment initiation), Day 1 cycle 2 (Day 21 +/- 3 days), Day 1 cycle 3 (Day 42 +/- 3 days) and progression.

Patients will be asked to provide samples of biopsy tissue at screening (prior to anticancer agent with immunomodulatory activity treatment initiation), during treatment (day 42 +/- 3 days) and at disease progression as follows. Tumor biopsy at inclusion is optional if materiel archived fixed in formalin and embedded in paraffin of diagnostic biopsy is available.

All randomized patients will be followed up until death or the end of the follow-up period, defined as 36 months after randomization, whichever occurs first. For all patients, treatments regimen, tumor response during and/or after treatment, survival follow-up will be collected on study database:

* Every 3 months until loco-regional relapse or metastasis evidence, death or until the date of study termination, whichever occurs first,
* Every 6 months after loco-regional relapse or metastasis evidence, until death or until the date of study termination, whichever occurs first.

Eligibility 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.

Primary outcomes:
measure: 1-year overall survival rate
timeFrame: 1 year
Secondary outcomes:
measure: Overall response rate within 6 months as per RECIST v1.1
timeFrame: throughout the treatment period, an expected average of 6 months
measure: Overall response rate at 6 months as per RECIST v1.1
timeFrame: 6 months
measure: Overall response rate as per RECIST v1.1
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Duration of overall response
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Best overall response rate as per RECIST v1.1
timeFrame: throughout the treatment period, an expected average of 1 year
measure: 2-year overall survival rate
timeFrame: 2 years
measure: 1-year progression-free survival rate
timeFrame: 1 year
measure: 2-year progression-free survival rate
timeFrame: 2 years
measure: Mean scores of each dimension of QLQ-C30 from EORTC quality of life group
timeFrame: at baseline, 3, 6, 9, 12 and 24 months
measure: Time to health-related quality of life score definitive deterioration (targeted dimension of EORTC QLQC30 : global health)
timeFrame: at baseline, 3, 6, 9, 12 and 24 months
measure: Number of patient receiving a post-progression treatment
timeFrame: an average of 6 months
measure: Overall response rate as per iRECIST
timeFrame: throughout the treatment period, an expected average of 6 months
measure: Duration of immune overall response
timeFrame: throughout the treatment period, an expected average of 1 year
measure: 1-year immune-progression-free survival rate
timeFrame: 1 year
measure: 2-year immune-progression-free survival rate
timeFrame: 2 year
measure: Best overall response rate as per iRECIST
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of immune-related SAEs (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of immune-related AEs (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of chemotherapy-related SAEs (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of chemotherapy-related AEs (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of cryoablation-related SAEs (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of cryoablation-related AEs (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of SAEs related to study procedures (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of AEs related to study procedures (CTCAE NCI V5)
timeFrame: throughout the treatment period, an expected average of 1 year
measure: Number of hospitalisations in experimental arm only
timeFrame: within 6 weeks + 30 days after first pembrolizumab administration
measure: Percentage of patients that worsen their ECOG score of 1 or more point
timeFrame: at follow-up visits post randomization (an average of 2 years)
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonié
state: Gironde
Study officials:
affiliation: Institut Bergonié
name: Jean PALUSSIERE, MD
role: PRINCIPAL_INVESTIGATOR
References: