An Open-label, Randomized, Parallel, Non Comparative, Phase II Trial of Nivolumab Plus Ipilimumab Versus Platinum-based Chemotherapy Plus Nivolumab in Chemonaive Metastatic or Recurrent Squamous-Cell Lung Cancer (SqLC) (SQUINT)

March 24, 2020 updated by: Fondazione Ricerca Traslazionale

SQUINT (Squamous Immunotherapy Nivolumab-Ipilimumab Trial): An Open-label, Randomized, Parallel, Non Comparative, Phase II Trial of Nivolumab Plus Ipilimumab Versus Platinum-based Chemotherapy Plus Nivolumab in Chemonaive Metastatic or Recurrent Squamous-Cell Lung Cancer (SqLC)

Non-small-cell Lung Cancer (NSCLC) remains the leading cause of cancer death in Western Countries. Approximately 85% of lung cancers are of the non-small-cell type (NSCLC), with 25-30% of NSCLC being squamous histology type. Unlike nonsquamous NSCLC, squamous NSCLC rarely harbors epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for which there are directed therapies, and until the recent approval of immunotherapies for pretreated squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced and metastatic squamous NSCLC. A platinum-based combination chemotherapy regimen has been the standard first-line treatment for all NSCLC. Carboplatin is frequently substituted for cisplatin for patients who have poor renal function or who experience toxicities from cisplatin (most notably, nausea and vomiting). Taxanes, especially paclitaxel, or vinorelbine or gemcitabine, commonly complete the standard two-drug backbone of platinum-based chemotherapy for the first-line treatment of NSCLC, with platin-gemcitabine as the most commonly used regimen in Europe in patients with squamous-histology. A recent press release announced that pembrolizumab plus chemotherapy produced higher response rate when compared to chemotherapy alone in patients with squamous-cell lung cancer. Nevertheless, no data on Progression-Free Survival (PFS) and Overall Survival (OS) are available. Therefore, considering the lack of data in patients with squamous histology and the lack of information about efficacy of combinations of immune-checkpoints inhibitors versus immune-checkpoint inhibitor plus chemotherapy, there is a strong rationale for conducting a study assessing efficacy of such strategies in patients with advanced, metastatic squamous-cell lung cancer.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. In the KEYNOTE 024 the anti-PD-1 inhibitor Pembrolizumab significantly prolonged progression-free survival (PFS) and overall survival (OS) of patients with advanced NSCLC and high PD-L1 level (>50% of tumor cells) compared to platinum based chemotherapy, thus becoming a new standard of care in front line setting. However, the trial was not restricted to squamous population, with approximately 18% per arm having this histology. Nivolumab, another PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial comparing the drug to docetaxel, in second-line setting. Importantly, the benefit produced by the drug was irrespective of PD-L1 expression suggesting that the high mutation burden of squamous-cell lung carcinoma is more relevant than the expression of a single biomarker, at least in pretreated individuals. In addition, recent studies in chemo naive patients with non-squamous histology demonstrated that combination of chemotherapy and immunotherapy is superior to chemotherapy alone in terms of Overall Survival irrespective of PD-L1 expression (Keynote 189 and IMPOWER 150). In addition, the CheckMate 227 study recently showed that, in chemonaive NSCLC, combination of nivolumab and ipilimumab was superior to chemotherapy alone in patients with high tumor mutational burden (TMB), irrespective of PD-L1 expression. A recent press release announced that pembrolizumab plus chemotherapy produced higher response rate when compared to chemotherapy alone in patients with squamous-cell lung cancer (Keynote 407). Nevertheless, no data on Progression-Free Survival and Overall Survival are available. Therefore, considering the lack of data in patients with squamous histology and the lack of information about efficacy of combinations of immune-checkpoints inhibitors versus immune-checkpoint inhibitor plus chemotherapy, there is a strong rationale for conducting a study assessing efficacy of such strategies in patients with advanced, metastatic squamous-cell lung cancer.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
112

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Arezzo, Italy, 52100
        • Not yet recruiting
        • Istituto Toscano Tumori Ospedale San Donato- U.O.C. di Oncologia Medica Dipartimento di Oncologia USL-8
        • Contact:
      • Genova, Italy, 16132
        • Not yet recruiting
        • IRCCS A.O.U. San Martino- IST- Istituto Nazionale per la Ricerca sul Cancro- U.O.S. Tumori Polmonari
        • Contact:
      • Milano, Italy, 20141
        • Recruiting
        • Istituto Europeo di Oncologia - Divisione di Oncologia Toracica
        • Contact:
      • Modena, Italy, 41124
        • Recruiting
        • A.O.U. Policlinico di Modena- Oncologia Ematologia e Malattie Apparato Respiratorio
        • Contact:
      • Napoli, Italy, 80131
        • Active, not recruiting
        • A.O.R.N dei Colli - Ospedale Monaldi
      • Padova, Italy, 35128
        • Recruiting
        • I.R.C.C.S. Istituto Oncologico Veneto
        • Contact:
        • Principal Investigator:
          • Laura Bonanno, MD
      • Palermo, Italy, 90127
        • Active, not recruiting
        • Azienda Ospedaliera Universitaria Paolo Giaccone
      • Palermo, Italy, 90146
        • Not yet recruiting
        • Casa di Cura La Maddalena- U.O. Oncologia medica
        • Contact:
      • Perugia, Italy, 06132
        • Recruiting
        • Azienda Ospedaliera di Perugia- S.C. Oncologia Medica
        • Contact:
        • Principal Investigator:
          • Vincenzo Minotti, MD
      • Ravenna, Italy, 48121
        • Recruiting
        • Ospedale di Ravenna- Oncologia Medica
        • Principal Investigator:
          • Federico Cappuzzo, MD
        • Contact:
      • Reggio Emilia, Italy, 42123
        • Recruiting
        • IRCCS Arcispedale Santa Maria Nuova
        • Principal Investigator:
          • Francesca Zanelli, MD
        • Contact:
      • Roma, Italy, 00152
        • Active, not recruiting
        • Azienda Ospedaliera San Camillo-Forlanini
      • Roma, Italy, 00152
        • Not yet recruiting
        • Policlinico Universitario "Campus Biomedico" di Roma
        • Contact:
      • Verona, Italy, 37134
        • Active, not recruiting
        • Policlinico 'G.B.Rossi' Borgo Roma - A.O.U. Integrata (Giampaolo Tortora)- Oncologia Medica
    • Forlì- Cesena
      • Meldola, Forlì- Cesena, Italy, 47014
        • Recruiting
        • IRCCS - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)- Oncologia Medica
        • Contact:
    • Italia
      • Rimini, Italia, Italy, 47900
        • Recruiting
        • Ospedale "Infermi" Rimini
        • Contact:
        • Contact:
          • Phone Number: 0541705413
        • Principal Investigator:
          • Maximilian Papi, MD
    • Potenza
      • Rionero In Vulture, Potenza, Italy, 85028
        • Not yet recruiting
        • Centro di Riferimento Oncologico della Basilicata
        • Contact:
    • Verona
      • Negrar, Verona, Italy, 37024
        • Recruiting
        • Sacro Cuore- Don Calabria Hospital- U.O.C. Oncologia Medica
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male and female patients willing and able to give written informed consent;
  • Histologically confirmed diagnosis of Stage IIIB-not amenable to radical treatment or Stage IV or recurrent squamous-cell lung carcinoma;
  • Tumor p63 (or p40) positive and TTF1 negative;
  • Availability of tumor tissue for PD-L1 expression analysis. One formalin-fixed paraffin embedded tumor tissue block or a minimum of 16 unstained tumor tissue sections are acceptable. The tumor tissue sample may be fresh or archival if obtained within 6 months prior to enrollment, and there can have been no systemic therapy (eg, adjuvant or neoadjuvant chemotherapy) given after the sample was obtained. Tissue must be a core needle biopsy, excisional or incisional biopsy. Fine needle biopsies or drainage of pleural effusions with cytospins are not considered adequate for biomarker review. Biopsies of bone lesions that do not have a soft tissue component or decalcified bone tumor samples are also not acceptable;
  • Availability of PD-L1 status;
  • Chemonaive patient. Adjuvant/neoadjuvant chemotherapy is allowed if therapy was completed at least 6 months before trial inclusion;
  • Performance status 0-1 (ECOG);
  • Patient compliance to trial procedures;
  • Age ≥ 18 years;
  • Written informed consent;
  • Adequate BM function (ANC ≥ 1.5x109/L, Platelets ≥ 100x109/L, HgB > 9g/dl);
  • Adequate liver function (bilirubin < G2, transaminases no more than 3xULN/<5xULN in present of liver metastases);
  • Normal level of alkaline phosphatase and creatinine;
  • If female: childbearing potential either terminated by surgery, radiation, or menopause, or attenuated by use of approved contraceptive method [intrauterine contraceptive device (IUD), birth control pills, or barrier device] during and for twenty-three (23) weeks after end of treatment;
  • If men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product;
  • Prior palliative radiotherapy to non-CNS lesions must have been completed at least 2 weeks prior to treatment. Patients with symptomatic tumor lesions that may require palliative radiotherapy within 4 weeks of first treatment are strongly encouraged to receive palliative radiotherapy prior to treatment. Patients are eligible if CNS metastases are adequately treated and patients are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization;
  • Patients must be either off corticosteroids, or on a stable or decreasing dose of ≥10 mg daily prednisone (or equivalent) for at least 2 weeks prior to randomization.

Exclusion Criteria:

  • No tumor tissue available;
  • Tumor negative for p63 (or p40) or positive for TTF1;
  • Previous chemotherapy for stage IV disease;
  • Adjuvant or neoadjuvant chemotherapy completed less than 6 months before trial inclusion; adjuvant or neoadjuvant immunotherapy is not allowed;
  • Concomitant radiotherapy or chemotherapy;
  • Untreated brain metastases;
  • Diagnosis of any other malignancy during the last 2 years, except for in situ carcinoma of cervix uteri and cutaneous squamous cell carcinoma;
  • Pregnancy or lactating;
  • Other serious illness or medical condition potentially interfering with the study.

Nivolumab and ipilimumab specific exclusion

  • Patients with an active, known or suspected autoimmune disease. Patients with type I diabetes mellitus; hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll;
  • Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease;
  • Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection;
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: ARM A: Nivolumab plus Ipilimumab
Immunotherapy will be given up to disease progression, toxicity or patient refusal and in any case for up to 24 months. Platinum-based chemotherapy will be given up to 6 cycles.
Drug: Nivolumab plus Ipilimumab
Nivolumab will be administered at the standard dose of 360 mg every 3 weeks. Ipilimumab will be administered at the dose of 1 mg/kg every 6 weeks.
Experimental: ARM B: Platinum-based chemotherapy plus Nivolumab
Platinum-based chemotherapy will be given up to 6 cycles. Immunotherapy will be given up to disease progression, toxicity or patient refusal and in any case for up to 24 months.
Drug: Platinum-based chemotherapy plus Nivolumab

Nivolumab will be administered at the standard dose of 360 mg every 3 weeks.

Platinum-based chemotherapy will be chosen by the investigator among the following regimens:

  • Cisplatin 80 mg/mq iv day 1 and Gemcitabine 1250 mg/mq iv days 1 and 8 every 21 days;
  • Carboplatin AUC 5 iv day 1 and Gemcitabine 1000 mg/mq iv days 1 and 8 iv every 21 days;
  • Carboplatin AUC 6 iv day 1 and paclitaxel 200 mg/mq iv day 1 every 21 days.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Efficacy in terms of Overall Survival in subjects with Stage IIIB not amenable to radical treatment or Stage IV or recurrent squamous-cell lung carcinoma treated in the study
Time Frame: 12 months
Overall Survival rate at 12 months in Arm A and B
12 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Biomarkers analysis
Time Frame: 48 months
Correlation of PD-L1 expression and/or TMB with outcome in Arm A and B
48 months
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 48 months
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
48 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Fondazione Ricerca Traslazionale

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Clinical Research Technology S.r.l.

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Federico Cappuzzo, Ospedale di Ravenna

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
September 13, 2017

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 28, 2021

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
February 28, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 2, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 29, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 30, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 24, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • SQUINT-FoRT 04

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings