INTENSE: A Phase I/II Study of INhomogeneous Targeted Dose Escalation in Non-Small CEll Lung Cancer

INTENSE: A Phase I/II Study of INhomogeneous Targeted Dose Escalation in Non-Small CEll Lung Cancer

This is a prospective non-randomised Phase I/II study with patients recruited to escalated dose cohorts. Escalated dose to the iGTV (internal gross tumour volume), with 60 Gy to the conventional PTV (planning target volume), will be delivered to successive cohorts of participants (6-12 participants/cohort) until the maximum tolerated oesophageal dose is determined. The minimum dose will be 60 Gy delivered via intensity modulated radiation therapy (IMRT) or volume modulated arc therapy (VMAT), planned on an Average Intensity Projection (AVIP) dataset.

Standard of care chemotherapy.

There will be two treatment arms; one with patients who are planned to receive neo-adjuvant or no chemotherapy, and the other with patients who are planned to receive concurrent chemotherapy.

This is a prospective non-randomised Phase I/II cohort study; please see above for Radiation Therapy and Chemotherapy treatment details

Each cohort will require a minimum of 6 and a maximum of 12 patients. Once 6 patients have been treated in a cohort a two-month break is taken before toxicity is analysed.

• If 2 or fewer patients experience a grade ≥3 toxicity, the next cohort will be enrolled and will receive an escalated dose (an additional +5 Gy at each escalation up to a maximum of 75 Gy)
• If 3 of the 6 patients experience a grade ≥3 toxicity, a further 6 patients will be recruited into that dose level
• If 4 or more patients experience a grade ≥3 toxicity then the MTD is fixed at the dose level of the previous cohort

If the cohort is extended to 12 patients, the following rules apply:

• If 4 or fewer patients experience a grade ≥3 toxicity, the next cohort will be enrolled and will receive an escalated dose.
• If 5 of the 12 patients experience a grade ≥3 toxicity, then the MTD is fixed at that dose level and recruitment continues up to a total of 24 patients at that dose level.
• If 6 or more patients experience a grade ≥3 toxicity, then the MTD is fixed at the dose level of the previous cohort.

Once the maximum dose cohort is established, patients will continue to be recruited at that dose level up to a total of 24 patients.

There will be two treatment arms; one with patients who are planned to receive neo-adjuvant or no chemotherapy, and th eother with patients who are planned to receive concurrent chemotherapy.

The concurrent and neo-adjuvant /no chemotherapy arms will then be escalated independently of each other.

For each arm the following number of patients will be required:

• Minimum number (if maximum dose level reached) = 36 (6 at 65 Gy, 6 at 70 Gy and 24 at 75 Gy)
• Maximum number (if maximum dose level reached) = 48 (12 at 65 Gy, 12 at 70 Gy and 24 at 75 Gy) A maximum of 48 patients are required to complete each arm (neo-adjuvant or none /concurrent chemotherapy) of the trial.

Acute toxicity will be assessed weekly during treatment and at 2, 4 and 8 weeks post-treatment Late toxicities will be assessed at 3, 6, 9, 12, 18 and 24 months post-treatment and annually thereafter until disease relapse / patient withdrawal / patient death.

Inclusion Criteria:

1. 18 years of age

2. ECOG (European Cooperative Oncology Group) performance status 0-2 (0-1 for concurrent chemotherapy)

3. Weight loss <10% within 3 months of diagnosis

4. Histological diagnosis (biopsy or cytology) of NSCLC (Squamous Cell Carcinoma (SCC), Adenocarcinoma, Large Cell).

   Eligible NSCLC stages: IIA (provided N1); IIB (including T3N0 if unresectable or unsuitable for stereotactic ablative body radiation therapy (SABR)); IIIA and IIIB

5. Inoperable (as per Multi-Disciplinary Team (MDT)) or patient refuses surgery

6. Respiratory function:

   Forced Expiratory Volume (FEV1) ≥ 1L or ≥ 40% of predicted Diffusing Capacity of Lung for Carbon Monoxide (DLCO) ≥ 40%

7. Radiological confirmation of disease via a Positron Emission Tomography (PET) scan prior to registration.

8. Life expectancy, from causes other than lung cancer, of greater than 12 months (as per physician's opinion)

9. Females of child bearing potential (see Appendix H) must not be pregnant and must be prepared to use adequate contraception methods during treatment. Males whose female partners are of child-bearing potential must be prepared to use adequate contraception methods during treatment. Examples of effective contraception methods are a condom or a diaphragm with spermicidal jelly, or oral, injectable or implanted birth control.

10. Provision of written consent in line with ICH-GCP guidelines

Exclusion Criteria:

1. Previous thoracic radiation therapy
2. Known co-existing or prior malignancy which is likely to interfere with treatment or assessment of outcomes
3. Known distant metastases or metastatic pleural effusion
4. Pancoast tumours (tumour of the pulmonary apex)
5. Supraclavicular nodal involvement
6. Spinal cord involvement
7. Patients with syndromes or conditions associated with increased radiosensitivity or development of lung fibrosis
8. Suitable for SABR
9. Idiopathic pulmonary fibrosis/usual interstitial pneumonia
10. Uncontrolled intercurrent illness that is likely to interfere with treatment or assessment of outcomes
11. Psychiatric illness/social situations that would limit compliance with study requirements
12. Pregnant or lactating at the time of proposed randomisation
13. Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study, or if it is felt by the research / medical team that the patient may not be able to comply with the protocol