PALEO

Protocol Title

PALliative oEsOphageal cancer chemoradioimmunotherapy (PALEO): A multicentre Phase II Clinical Trial

AIM

PALEO is a single arm, multicentre Phase II trial in adults with previously untreated oligometastatic oesophageal or gastro-oesophageal (GOJ) carcinoma and symptomatic dysphagia. The trial objective is to assess the efficacy and tolerability of concurrent palliative chemoradiotherapy and anti-PD1/PDL1 immunotherapy in patients with oligometastatic oesophageal and GOJ cancer.

All participants will receive 2 weeks of therapy with concurrent hypofractionated radiotherapy (30Gy/10 fractions), weekly carboplatin AUC2, weekly paclitaxel 50mg/m2 and q2weekly anti-PD1/PDL1 immunotherapy, followed by anti-PD1/PDL1 monotherapy continuing 2 weekly for up to 12 months.

For further immune priming, stereotactic radiotherapy (24Gy/3 fractions) to a single metastasis will be delivered 4 weeks post chemoradiotherapy completion.

Primary endpoints are continued improvement in dysphagia Mellow score at 6 months and progression free survival. Secondary endpoints are maximum improvement in Mellow score, nutritional status change, QOL, endoscopic response, response rate in metastatic lesions, toxicity and overall survival.

Background

The typical presentation of oesophageal or gastro-oesophageal (GOJ) cancer is with dysphagia (difficulty swallowing) due to the primary tumour. On subsequent staging investigations the majority of patients will be diagnosed with de novo metastatic disease, for which there is no accepted standard of care in the setting of a symptomatic primary tumour. Patients require expeditious and effective relief of their dysphagia within an overall treatment plan that is palliative in intent. Treatment options include best supportive care, chemotherapy, radiotherapy, stenting, or a combination of these.

Clinical goals in the palliative setting include return to normal function, minimally toxic therapy, durable treatment responses, patient quality of life and prolonged survival.

In a recent Phase I clinical trial we have completed in this patient group, we have shown that first line concurrent chemoradiotherapy (30Gy) with low dose weekly carboplatin and paclitaxel can be safely hypofractionated from 15 to 10 fractions, thereby reducing the treatment burden to the patient and health system.

Of the 15 patients with at least 6 weeks follow up, all have achieved improvement in their dysphagia, and the majority have returned to a normal diet. At least 3 patients have achieved complete relief of their dysphagia beyond 1 year. In the current proposal, we aim to further prolong the dysphagia relief provided by our well-tolerated 2 week CRT protocol while simultaneously providing distant disease control.

Clinical Trial Design 

The Phase II PALEO clinical trial adds concurrent checkpoint inhibition with single agent anti-PD1/PDL1 monoclonal antibody therapy to chemoradiotherapy, and then continuing for up to 12 months. Stereotactic radiotherapy (SBRT) is delivered to a single metastasis post-chemoradiotherapy. Despite the high mutational burden of oesophagogastric cancer, 2 single agent immune-oncology treatment has to date provided low response rates, 3 hence the importance of steps to ‘prime’ the immune response. We combine three strategies to both maximise clinical benefit and concurrently increase tumour antigen presentation:

• Radiotherapy to the primary tumour (explained subsequently)
• Use of paclitaxel, an immunogenic chemotherapy in the presence of radiotherapy4
• 24Gy in 3 fractions of stereotactic radiotherapy to a metastasis, given the different immune milieu of metastases, the immunogenicity of this radiation dose fractionation and early promising data suggesting an increased response rate to checkpoint inhibition with this approach.5-7

We hypothesise that this treatment combination will provide durable dysphagia relief and progression free survival with a tolerable toxicity profile. The therapeutic strategy is supported by pre-clinical8 and clinical data9-11 showing that radiotherapy increases the presentation of tumour-associated antigens which prime CD8+ T cells.12 The resultant increased immunogenicity of the malignancy, both at the irradiated site and in distant metastases, may be further augmented by immune checkpoint inhibition.13 The application of anti-PD1/PDL1 immunotherapy also capitalises on the favourable side effect profile of these agents14,15, shown in multiple randomised controlled trials (RCTs) to be better tolerated than typical platinum-based chemotherapy.16,17 Our target patient cohort has oligometastatic disease and weight loss of <10% based on data from the Australian TROG 03.01 Phase III RCT in patients with advanced/metastatic oesophageal cancer, which found these characteristics prognostic.18 We have further defined the metastatic disease as non-bulky and not requiring immediate cisplatin/oxaliplatin-based systemic chemotherapy in the judgement of the treating clinician, in line with the patient cohort recruited to our Phase I study.

PATIENTS RECRUITED

Click to access the table and view recruitment data on all AGITG open trials:

Open Trial Recruitment Table

Key Eligibility Criteria

Inclusion criteria:

1. Biopsy proven carcinoma of the oesophagus or gastro-oesophageal junction
2. Oligometastatic disease (1-5 lesions outside radiotherapy field on FDG-PET)
3. Symptomatic dysphagia (Mellow score >0)
4. ECOG performance status 0-2
5. Loss of weight <10%

Exclusion criteria:

1. Bulky or organ-threatening metastatic disease requiring higher dose chemotherapy in the judgement of the treating clinician
2. Tumour HER2 positivity
3. Contra-indications to carboplatin, paclitaxel or immunotherapy
4. Oesophageal stent in situ
5. Previous systemic therapy for oesophageal or GOJ carcinoma/Previous thoracic RT

Principal Investigators

Dr Fiona Day and Professor Jarad Martin

Detailed Information Available on

More detailed information available online at the Australian New Zealand Clinical Trial Registry (ANZCTR)