Clinical trial NCT01537991: ISoToxic Accelerated RadioTherapy in Locally Advanced Non-small Cell Lung Cancer: The Phase I/II I-START Trial
Official title: A Phase I/II Trial of Isotoxic Accelerated Radiotherapy in the Treatment of Patients With Non-small Cell Lung Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Locally Advanced Non-small Cell Lung Cancer
Keywords: radiotherapy
non small cell lung cancer
isotoxic
Lead sponsor: Velindre NHS Trust
Sponsor class: OTHER_GOV
First posted: 2012-02-23
Enrollment: 81
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The I-START trial is designed to determine the highest doses of radiotherapy that can safely be used in locally advanced non-small cell lung cancer (NSCLC). Patients with NSCLC who are expected to live longer than three months and are fit to receive radical radiotherapy (radiotherapy given with curative intent) will be eligible to participate. All trial participants will receive 20 doses (called fractions) of radiotherapy. Evidence is available that suggests increasing the dose of radiotherapy given per fraction may improve both local control of the cancer and survival in some patients. However, high dose radiotherapy can damage normal tissues as well as the tumour. The dose of radiotherapy that can be used to treat lung cancer is limited by the normal tissues close to the cancer. For most of these normal tissues (lung, spinal cord and heart) the maximum safe radiotherapy dose that can be given is known. The maximum safe dose of radiotherapy for the oesophagus (gullet) is not currently known.

The trial will be split into two parts:

1. For those participants where the oesophagus will receive a high dose of radiation due to it lying close to the cancer, the first part of the trial will establish the maximum safe dose of radiotherapy to the oesophagus. The first group of participants will receive a slightly higher dose than is currently used to treat lung cancer. If these participants do not have any significant side effects, a second group of participants will receive a slightly higher dose than the first group. This process will continue incrementally until side effects from the treatment become evident, thus demonstrating the maximum dose that can safely be given. Once the maximum safe dose to the oesophagus is known this will be classed as the recommended Phase II dose and all further patients entering the trial will receive no more than this dose to the oesophagus.
2. For those participants where the cancer is a safe distance from their oesophagus, the highest dose of radiotherapy that does not exceed the known safe dose limits of the normal structures (lung, spinal cord and heart) will be used.

The findings of both parts of this study will determine whether increasing the dose of radiotherapy for NSCLC patients is a tolerable, safe and effective treatment. If the results are positive then this new treatment may be compared against the best currently available standard treatments in a future larger randomised (Phase III) trial.

Detailed description: Main inclusion criteria:

1. Histologically or cytologically confirmed stage II - IIIb NSCLC (see appendix II)
2. Inoperable disease (as assessed by a lung cancer MDT with thoracic surgical input) or operable but the patient refuses surgery
3. Disease which can be encompassed within a radical radiotherapy treatment plan in keeping with standard practice at the participating centre
4. WHO Performance Status 0 or 1 (Appendix III)
5. Adequate respiratory function: FEV1 ≥ 1.0 litre, DLco (transfer factor) ≥ 40% of predicted and Kco (DLco/VA) \> 40% predicted on baseline lung function tests
6. Blood Haemoglobin ≥ 10g/dL
7. No prior thoracic radiotherapy
8. Age ≥ 16 years
9. Considered fit to receive trial treatment
10. Estimated life expectancy of more than 3 months
11. Written informed consent obtained
12. Patient consents for electronic CT scan and planning data to be used for future research

Main exclusion criteria:

1. Medically unstable (e.g. unstable diabetes, uncontrolled hypertension, infection, hypercalcaemia or very symptomatic ischaemic heart disease)
2. Previous or current malignant disease likely to interfere with protocol treatment
3. Pancoast tumours
4. Connective tissue disorders (e.g. Scleroderma, Systemic Lupus Erythematosus)
5. Interstitial lung disease
6. Women who are pregnant or lactating
7. Women of childbearing potential who are not using adequate contraceptive precautions

   Primary outcome measure:

   Phase I:

   • Establish the maximum tolerated dose (MTD) to the oesophagus to use as the recommended Phase II dose.

   Phase II:

   • Toxicity rate (grade 3 and 4) at three months.

   Secondary outcome measures

   Phase I:

   • Chronic oesophagitis or stricture occurring/persisting two months or more after completion of radiotherapy

   Phase II:
   * Local control at three months (to include complete response, partial response and stable disease)
   * Feasibility
   * Time to Local Progression; measured in days from the day of trial entry to the date of first clinical evidence of progressive disease at the primary site
   * Time to distant metastases measured in days
   * Overall Survival; measured in days, from the day of trial entry to the day of death (from any cause)
   * Toxicity; pulmonary, oesophageal, spinal cord and cardiac grade 3 or 4 toxicity occurring up to three months after radiotherapy
   * Radiotherapy Quality Assurance. A detailed QA program will be in place to ensure adherence to the protocol. Major and minor deviations will be documented

Eligibility criteria: Inclusion Criteria:

1. Histologically or cytologically confirmed stage II - IIIb NSCLC (see appendix II)
2. Inoperable disease (as assessed by a lung cancer MDT with thoracic surgical input) or operable but the patient refuses surgery
3. Disease which can be encompassed within a radical radiotherapy treatment plan in keeping with standard practice at the participating centre
4. WHO Performance Status 0 or 1 (Appendix III)
5. Adequate respiratory function: FEV1 ≥ 1.0 litre, DLco (transfer factor) ≥ 40% of predicted and Kco (DLco/VA) \> 40% predicted on baseline lung function tests
6. Blood Haemoglobin ≥ 10g/dL
7. No prior thoracic radiotherapy
8. Age ≥ 16 years
9. Considered fit to receive trial treatment
10. Estimated life expectancy of more than 3 months
11. Written informed consent obtained
12. Patient consents for electronic CT scan and planning data to be used for future research
13. Patient is available for follow up

Exclusion Criteria:

1. Medically unstable (e.g. unstable diabetes, uncontrolled hypertension, infection, hypercalcaemia or very symptomatic ischaemic heart disease)
2. Previous or current malignant disease likely to interfere with protocol treatment
3. Pancoast tumours
4. Connective tissue disorders (e.g. Scleroderma, Systemic Lupus Erythematosus)
5. Interstitial lung disease
6. Women who are pregnant or lactating
7. Women of childbearing potential who are not using adequate contraceptive precautions

Primary outcomes:
measure: Phase I: Establish the maximum tolerated dose (MTD) to the oesophagus to use as the recommended Phase II dose.
timeFrame: toxicity assessed up to 60 days after last Radiotherapy dose
measure: Phase II: Toxicity rate (grade 3 and 4) at three months.
timeFrame: 3 months
Secondary outcomes:
measure: Phase I: Chronic oesophagitis or stricture occurring/persisting two months or more after completion of radiotherapy
timeFrame: 2 months
measure: Pase II: Local control at three months (to include complete response, partial response and stable disease)
timeFrame: 3 months
measure: Phase II: Feasibility
timeFrame: 2 years
measure: Phase II: Time to Local Progression; measured in days from the day of trial entry to the date of first clinical evidence of progressive disease at the primary site
timeFrame: 2 years
measure: Phase II: Time to distant metastases measured in days
timeFrame: 2 years
measure: Phase II: Overall Survival; measured in days, from the day of trial entry to the day of death (from any cause)
timeFrame: 2 years
measure: Phase II: Toxicity; pulmonary, oesophageal, spinal cord and cardiac grade 3 or 4 toxicity occurring up to three months after radiotherapy
timeFrame: 3 months
measure: Phase II: Radiotherapy Quality Assurance. A detailed QA program will be in place to ensure adherence to the protocol. Major and minor deviations will be documented
timeFrame: 2 years
Other outcomes:
Locations:
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
state: Glamorgan
city: Liverpool
country: United Kingdom
facility: Clatterbridge Centre for Oncology
state: Merseyside
Study officials:
affiliation: Velindre Cancer Centre
name: Jason Lester, MBBS, MRCP, FRCR
role: PRINCIPAL_INVESTIGATOR
affiliation: Wales Cancer Trials Unit
name: Gareth Griffiths, BSc, MSc, Cstat
role: STUDY_DIRECTOR
References: