Clinical trial NCT05078047: Study Comparing the Standard Administration of IO Versus the Same IO Administered Each 3 Months in Patients in Response After 6 Months of Standard IO
Official title: Randomized Phase III Trial of Standard Immunotherapy (IO) by Checkpoint Inhibitors, Versus Reduced Dose Intensity of IO in Patients With Locally Advanced or Metastatic Cancer in Response After 6 Months of Standard IO
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Lung Cancer Metastatic
Renal Cell Carcinoma
Head and Neck Cancer
Triple Negative Breast Cancer
Merkel Cell Carcinoma
Hepatocellular Carcinoma
Melanoma
Urothelial Carcinoma
Colorectal Carcinoma With Microsatellite Instability
Esophageal Squamous Cell Carcinoma
Endometrial Carcinoma
Cervical Cancer
Gastric/Gastro-esophageal Junction/Esophageal Adenocarcinoma
Basal Cell Carcinoma
Squamous Skin Carcinoma
Keywords: Immunotherapy
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2021-10-14
Enrollment: 646
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomized 1:1 into two arms:

• Experimental arm: Reduced dose intensity of IO

IO will be administered every 3 months (at the same dose levels) until disease progression, unacceptable toxicity, death or patient's choice or investigator's decision.

• Control arm: Standard IO

Continuation of IO at the same dose levels and rhythmicity until disease progression, unacceptable toxicity, death or patient's choice.

Random allocation will be stratified by tumour type, by response status (partial response versus complete response) evaluated 6 months after the initiation of standard IO, by treatment line (first line vs others), and by type of IO
Primary purpose: TREATMENT

Brief summary: Immunotherapy (IO), such as treatment with anti-PD-1, PD-L1, or CTLA-4 inhibitors, is a rapidly expanding treatment for multiple metastatic cancers with improved survival for certain cancers. However, the optimal duration of immunotherapies is currently unknown. Our hypothesis is that a reduced dose intensity of IO could be as effective as the current standard treatment in term of prevention of the disease progression. If proved right, this study will have a positive medico-economic impact by reduction of the costs associated with the treatment and the toxicity, and an increase of the patients' quality of life.

Detailed description: Immunotherapy (IO) is a rapidly expanding treatment for multiple metastatic cancers with improved survival for certain cancers. For currently approved immunotherapies such as PD-1 / PD-L1 inhibitors and anti-CTLA-4, the rhythm and duration of treatment are recommended until disease progression or unacceptable toxicity. However, the optimal duration of these treatments is currently unknown.

No major dose-dependent effect of anti-PD-1 have been observed and whether the frequency of infusion of IO could improve response or maintain efficacy. Moreover, phase I studies have shown that saturation of the target (PD-1 or PD-L1) can persist far beyond the serum half-life of the IO and 3-monthly infusions of an anti-PD-1 antibody could potentially generate the same level of activity as infusions administered every 2 weeks.

In silico modeling studies have suggested that alternate scheduling with IO couldn't compromise the efficacy of the treatment. Indeed, prolonged half-lives of IO drugs, time-varying clearance plus plasma concentrations far above the threshold associated with maximal target-engagement, suggest that the rhythm of administration of IO could be slowed down.

Without substantial international data for responding patients, apart metastatic melanoma in complete response, patients and physicians are afraid of stopping treatment, by fear of relapse. Over-treatment with IO may be toxic and inefficient. The rising cost of cancer care in the era of immunotherapy is of great concern for public and private payers around the world.

Chronic administration has important consequences for patients and health systems, with multiple medical visits and the risk of chronic, progressive and sometimes fatal toxicities induced by immunotherapy.

This is a pragmatic and strategic study challenging the routine practice which compares for the first time in a randomized phase III study, the standard administration of IO versus the same agent administered each three months in patients with metastatic cancer in partial or complete response after 6 months of standard IO ( except melanoma in CR).

If our hypothesis of non-inferiority of PFS with a reduced dose intensity of IO is verified, this could replace standard treatment and have a positive medico-economic impact, allowing, on the one hand, a reduction of the costs associated with the treatment and the toxicity, and on the other hand, an increase of the patients' quality of life.

Eligibility criteria: Inclusion Criteria:

1. Patients must have signed a written informed consent form prior to any trial specific procedures.
2. Patient aged ≥18 years old.
3. Metastatic disease (or locally advanced disease not suitable for local treatment) of initial tumor histologically confirmed including: lung cancer, renal cell cancer, head and neck cancer, urothelial carcinoma, triple negative breast cancer, Merkel cancer, hepatocellular carcinoma, melanoma, colorectal carcinoma with microsatellite instability \[MSI\], esophageal squamous cell carcinoma, endometrial carcinoma,cervical cancer, gastric/gastro-oesophageal junction adenocarcinoma, basal cell carcinoma or squamous skin carcinoma.
4. Patients in partial or complete response after 6 months of standard immunotherapy (whatever the line of therapy) according to the RECIST or PERCIST v1.0 criteria (confirmed by local radiological assessment).

   For metastatic melanoma only patients in partial response. Patients with metastatic or advanced cancer treated by immunotherapy as maintenance therapy can be included without any lesion at IO initiation. In this case, response after 6 months of standard immunotherapy will be evaluated by the non-appearance of a new lesion.
5. Eligible to maintain the same standard IO treatment.
6. Patient with Eastern cooperative oncology group (ECOG) performance status ≤1.
7. Patients with brain metastases are allowed, provided they are stable according to the following definitions: treated with surgery or stereotactic radiosurgery and without evidence of progression prior to randomization and have no evidence of new or enlarging brain metastases.
8. Patients treated by IO previously combined with chemotherapy are allowed.
9. Patients with Tyrosine Kinase Inhibitor (TKI)-IO or pemetrexed-IO or bevacizumab-IO are allowed.
10. Evidence of post-menopausal status, or negative urinary or serum pregnancy test for pre-menopausal patients.
11. Both sexually active women of childbearing potential and males (and their female partners) patients must agree to use adequate contraception method for the duration of the study treatment and after completing treatment according to the most recent version of the IO Summary of product characteristics (SmPC).
12. Patient is willing and able to comply with the protocol for the duration of the trial including undergoing treatment and scheduled visits, and examinations including follow-up.
13. Patient must be affiliated to a Social Security System.

Exclusion Criteria:

1. Metastatic melanoma in complete response.
2. Metastatic renal cell carcinoma with International Metastatic Renal Cell Carcinoma Database (IMDC) favourable-risk treated TKI/IO combination.
3. Hematologic malignancies (leukaemia, myeloma, lymphoma...)
4. Active infection requiring systemic therapy.
5. Patients enrolled in another therapeutic study within 30 days before the inclusion in and during MOIO study.
6. Patient unable to comply with study obligations for geographic, social, or physical reasons, or who is unable to understand the purpose and procedures of the study.
7. Person deprived of their liberty or under protective custody or guardianship.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: From randomization to disease progression or death, up to 3 years
Secondary outcomes:
measure: Cost-effectiveness analysis of the proposed therapeutic strategy
timeFrame: 3 years
measure: Immune progression-free survival (iPFS)
timeFrame: From randomization to disease progression or death, up to 3 years
measure: Objective response rate (ORR)
timeFrame: From randomization to 12 and 24 months post-randomization
measure: Overall survival (OS)
timeFrame: From randomization to death from any cause, up to 3 years
measure: Duration of response (DoR)
timeFrame: From randomization to disease progression or death, up to 3 years
measure: Quality of life questionnaire - Core 30 (QLQ-C30)
timeFrame: At inclusion visit (pre-randomization) and 3, 6, 9, 12, 15, 18, 24, and 36 months post-randomization
measure: The Developed 5-level version of EQ-5D (EQ-5D-5L) questionnaire
timeFrame: At inclusion visit (pre-randomization) and 3, 6, 9, 12, 15, 18, 24, and 36 months post-randomization
measure: Hospital anxiety and depression scale (HADS)
timeFrame: At inclusion visit (pre-randomization) and 3, 6, 9, 12, 15, 18, 24, and 36 months post-randomization
measure: Fear of relapse questionnaire
timeFrame: At inclusion visit (pre-randomization) and 3, 6, 9, 12, 15, 18, 24, and 36 months post-randomization
measure: Safety profile
timeFrame: At 12 months and 3 years post-randomization
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de cancérologie de l'Ouest
city: Avignon
country: France
facility: Clinique Sainte Catherine
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte Basque
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: CHU Bordeaux - Hôpial Saint André
city: Boulogne-sur-Mer
country: France
facility: CH Boulogne sur Mer
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal
city: Créteil
country: France
facility: CHU Henri Mondor
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Grenoble
country: France
facility: GH Mutualiste de Grenoble
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: Clinique Chenieux
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hôpital La Timone -APHM
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: CHU Nîmes/Institut de cancérologie du Gard
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital Cochin APHP
city: Paris
country: France
facility: Hôpital Saint Antoine APHP
city: Poitiers
country: France
facility: CHU Poitiers
city: Reims
country: France
facility: Insitut Godinot
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Saint-Aubin-lès-Elbeuf
country: France
facility: CHI Elbeuf
city: Saint-Cloud
country: France
facility: Institut Curie
city: Saint-Herblain
country: France
facility: Institut de cancérologie de l'Ouest
city: Saint-Lô
country: France
facility: Centre Hospitalier Mémorial de Saint-Lô
city: Saint-Nazaire
country: France
facility: Clinique Mutualiste de l'Estuaire
city: Strasbourg
country: France
facility: ICANS
city: Suresnes
country: France
facility: Hôpital Foch
city: Toulon
country: France
facility: HIA Sainte Anne
city: Toulouse
country: France
facility: IUCT
city: Tours
country: France
facility: CHU Bretonneau
city: Villejuif
country: France
facility: Centre Gustave Roussy
Study officials:
affiliation: Institut Paoli-Calmettes, Marseille
name: Gwenaëlle GRAVIS-MESCAM, MD
role: PRINCIPAL_INVESTIGATOR
References: