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Inhibition of CArbonic Anhydrase in Combination With Platinum and Etoposide-based Radiochemotherapy in Patients With Localized Small Cell Lung Cancer (ICAR)

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ClinicalTrials.gov Identifier: NCT03467360
Recruitment Status : Recruiting
First Posted : March 16, 2018
Last Update Posted : October 30, 2019
Sponsor:
Information provided by (Responsible Party):
Centre Antoine Lacassagne

Brief Summary:

The investigators propose to study the carbonic anhydrase inhibition (acetazolamide) associated with concomitant radiochemotherapy in localized small cell lung cancer due to:

  1. The over-expression of carbonic anhydrases in this type of cancer,
  2. The Anti-tumor effect in preclinical acetazolamide in various tumor lines including neuroendocrine tumor lines,
  3. The observed synergy between irradiation and inhibition of carbonic anhydrases,
  4. Potential anti-tumor immune effect caused by decreased extracellular acidity.

Condition or disease Intervention/treatment Phase
Small Cell Lung Cancer Drug: acetazolamide in combination with platinum and etoposide-based radiochemotherapy Phase 1

Detailed Description:

Compared with healthy cells, glucose metabolism is greatly modified in cancer cells because of their highly proliferative character. This differential tumor / healthy tissue property is an opportunity to be able to propose a treatment whose therapeutic gain can be major (targeted treatment). Preclinical studies are multiple and showed that the targeting of overexpressed proteins (carbonic anhydrases) and involved in glycolytic metabolism can lead to a significant anti-tumor effect. This has never been tested in humans.

Acetazolamide is a molecule commonly used for non carcinologic purposes but has demonstrated anti-tumor activity in preclinical studies; there is also synergy radiotherapy / targeting of carbonic anhydrases. Therefore, the investigators propose to study the combination of acetazolamide / radiotherapy / chemotherapy with platinum and etoposide in localized Small Cell Lung cancer.

This would be the first study:

  • targeting glucose metabolism,
  • testing the effectiveness of acetazolamide in oncology,
  • testing the synergy radiotherapy / targeting glycolytic metabolism,
  • trying to manipulate the anti-tumor immune system indirectly, by decreasing extracellular acidosis.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Phase I study with a prospective, multicenter, non randomized, open-label extension cohort, evaluating the safety of acetazolamide in combination with platinum and etoposide-based radiochemotherapy in patients with Localized Small cell lung cancer
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Trial of Carbonic Anhydrase Inhibition Associated With Chemotherapy With Cisplatin and Etoposide in Concomitance With Radiotherapy in Localized Small Cell Lung Carcinomas
Actual Study Start Date : August 2, 2019
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : November 30, 2023


Arm Intervention/treatment
Experimental: One experimental arm
non randomized, open-label extension cohort, evaluating the safety of acetazolamide in combination with platinum and etoposide-based radiochemotherapy in patients with Localized small lung cancer
Drug: acetazolamide in combination with platinum and etoposide-based radiochemotherapy
Radiation therapy will be combined with platinum and etoposide-based chemotherapy combined with 3-6 tablets per day of acetazolamide during the entire course of therapy (dosage appropriate to the inclusion phase).




Primary Outcome Measures :
  1. To identify the Tolerated Maximum Dose (DMT) and Recommended Dose (DR) of acetazolamide in combination with radiotherapy combined with platinum and etoposide chemotherapy [ Time Frame: 32 months ]
    The frequency of limiting dose toxicities determined by the number of Adverse Events as Assessed by CTCAE v4.03 during the 6 weeks of treatment with acetazolamide / chemoradiation based on platinum and etoposide and in the first 6 months of follow-up after the last administration of the treatment


Secondary Outcome Measures :
  1. To determine the overall tolerance of the association acetazolamide and radiochemotherapy [ Time Frame: 27 months ]
    The overall tolerability of the association acetazolamide and radiochemotherapy during the duration of patient participation will be measured by clinical (performance status), laboratory (blood sample), and paraclinical evaluations (ETT, EFR) and defined on the NCI CTCAE V4.03 scale

  2. To evaluate the effectiveness of the treatment [ Time Frame: 24 months ]
    The tumor response (complete or partial, stabilization, progression) will be performed by Morphological evaluations using a scanner according to RECIST 1.1 criteria

  3. To evaluate the effectiveness of the treatment [ Time Frame: 24 months ]
    The tumor response (complete or partial, stabilization, progression) will be performed by Metabolic evaluations using a PET-CT scan according to the criteria PERCIST 1.0

  4. To identify predictive factors for response to acetazolamide [ Time Frame: 30 months ]

    The evaluation of predictive factors of acetazolamide response will be determined by:

    o Initial serum CAIX and CAXII levels, in the 7 days before the start of chemoradiotherapy associated with acetazolamide and the end-of-treatment visit


  5. To identify predictive factors for response to acetazolamide [ Time Frame: 30 months ]

    The evaluation of predictive factors of acetazolamide response will be determined by:

    o The initial 18-FDG PET-CT scan (SUVmax, SULpeak) fixation intensity and 3 months after treatment,


  6. To evaluate progression-free survival at 24 months [ Time Frame: 24 months ]
    To determine the delay between the date of inclusion and the date of progression or death

  7. To evaluate overall survival at 24 months [ Time Frame: 24 months ]
    To determine the delay between the date of inclusion and the date of death

  8. To determine the compliance of acetazolamide [ Time Frame: 27 months ]
    Compliance assessment will be done using Girerd's questionnaire

  9. To evaluate the quality of life [ Time Frame: 27 months ]
    Quality of life will be determined using EORTC QLQC30 questionnaire



Information from the National Library of Medicine

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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:

  • Age > or = 18 years,
  • Performance Status 0 to 2,
  • Patient with an histologically non-metastatic localized Small cell lung cancer,
  • Patient who must start radiotherapy treatment combined with chemotherapy with platinum and etoposide, Note: The decision of the Multidisciplinary Consultation Team must be notified in the patient's medical file,
  • Evaluation lesion according to the criteria RECIST 1.1 and / or according to the criteria PERCIST 1.0,
  • Women of childbearing potential must have a negative serum pregnancy test within 72 hours of the first administration of the study treatment,
  • If the patient is a woman of childbearing potential, she must be surgically sterile or agree to use two adequate methods of contraception throughout the duration of the study until 1 month after the last administration of the study treatment. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year, Note: Abstinence is acceptable if it is the patient's usual and preferred form of contraception,
  • If the male patient has one or more female partners of childbearing age, he / she must agree to use an adequate method of contraception, starting at the first administration of the study treatment up to 1 month after the last administration of the treatment. of the study, Note: Abstinence is acceptable if it is the patient's usual and preferred form of contraception,
  • Patient willing and able to provide written informed consent/assent for the trial,
  • Patient affiliated with a health insurance system.

Exclusion Criteria:

  • Patient with metastatic disease,
  • History of thoracic irradiation or near / in the thoracic irradiation field,
  • Patient who refuses to participate in the study or unable to agree,
  • Contraindication to thoracic radiotherapy treatment: congestive heart failure unbalanced (ejection fraction <30%, clinical signs), severe respiratory failure:

    • COPD grade IV according to the GOLD classification,
    • Some GOLD III COPD and any patient with a respiratory defect defined as: oxygen dependence and / or FEV1 <40% normal and / or, DLCO <40% predictive value and / or vital capacity <40% predictive value,
  • Contraindication to acetazolamide: hypersensitivity to acetazolamide, severe hepatic, renal or adrenal insufficiency, sulfonamide intolerance, history of renal colic, allergy to wheat other than celiac disease,
  • Patient currently receiving one or more treatments described in section 6.9 of the protocol,
  • History of cancer, with the exception of cancers in complete remission for more than 5 years, completely resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer,
  • People particularly vulnerable as defined in Articles L.1121-5 to -8 of the French Healthcare Code, including: person deprived of freedom by an administrative or judicial decision, adult being the object of a legal protection measure or outside a state to express their consent, pregnant or breastfeeding women

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): NCT03467360


Contacts
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Contact: Jérôme Doyen, MD +33492031270 jerome.doyen@nice.unicancer.fr
Contact: Michel Poudenx, MD +33492031129 michel.poudenx@nice.unicancer.fr

Locations
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France
Centre Antoine Lacassagne Recruiting
Nice, France, 06189
Contact: Jérôme Doyen, MD    +33492031270    jerome.doyen@nice.unicancer.fr   
Sponsors and Collaborators
Centre Antoine Lacassagne
Investigators
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Study Chair: Christine Lovera Centre Antoine Lacassagne

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Responsible Party: Centre Antoine Lacassagne
ClinicalTrials.gov Identifier: NCT03467360     History of Changes
Other Study ID Numbers: 2017/14
First Posted: March 16, 2018    Key Record Dates
Last Update Posted: October 30, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Small Cell Lung Carcinoma
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Etoposide
Etoposide phosphate
Acetazolamide
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticonvulsants
Carbonic Anhydrase Inhibitors
Diuretics
Natriuretic Agents
Physiological Effects of Drugs