Clinical trial NCT06290505: A Trial of Palliative Chemotherapy, Radiation and Immune Treatment for Oesophageal Cancer: PALEO Study
Official title: PALEO: Phase II Clinical Trial of Chemoradioimmunotherapy for the ALleviation of oEsOphageal Cancer Complications
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Esophageal Cancer
Lead sponsor: Australasian Gastro-Intestinal Trials Group
Sponsor class: NETWORK
First posted: 2024-03-04
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate the effects of the addition of the stereotactic body radiotherapy and durvalumab to a well tolerated 2 week chemotherapy and radiation treatment regimen in people with esophageal cancer that is locally advanced or has spread to another area of the body (metastasized).

Detailed description: The purpose of this study is to investigate the effects of the addition of the stereotactic body radiotherapy and durvalumab to a well tolerated 2 week chemotherapy and radiation treatment regimen in people with esophageal cancer that is locally advanced or has spread to another area of the body (metastasized).

Who is it for?

Participant may be eligible for this study if participant is an adult who has cancer of the esophagus or gastro-esophageal junction that is locally advanced or has spread to other parts of the participant's body.

Study details

All participants in this study will receive 10 treatments of radiotherapy to the primary esophageal cancer, with one treatment given on each working day for two weeks. In addition, all participants will receive chemotherapy (including carboplatin and paclitaxel) given intravenously once per week for the same two weeks as the radiotherapy. Durvalumab, an immune therapy, received intravenously; will be given every four weeks from the beginning of radiation therapy.

After this participants will continue to receive immune therapy (durvalumab), received intravenously once every 4 weeks for up to 24 months or until the cancer worsens. If participants have a metastatic tumour, they will also be given 3 doses of radiotherapy in one week. This radiotherapy will be received 4 weeks after the initial radiotherapy is completed.

Safety blood tests will be collected throughout the study (every two weeks from week 2 of treatment and then every four weeks from week 9 throughout the treatment and at other times if clinically indicated). CT scans to evaluate the response to treatment will be done every 6 weeks up to week 24 of treatment and then every 12 weeks or until the cancer worsens. Study participants will also be asked to complete some questionnaires about their wellbeing and nutritional status periodically throughout the study.

It is hoped that this trial can help determine if this chemotherapy with immune therapy and radiotherapy combination is effective in increasing the ability of the body's immune system to prevent worsening of the cancer and improve swallowing.

Eligibility criteria: Inclusion Criteria:

1. Males and females \> 18 years of age.
2. Biopsy proven adenocarcinoma or squamous cell carcinoma of the esophagus or gastro-oesophageal junction
3. Oligometastatic disease (1-5 lesions outside the primary tumour radiotherapy field on FDG-PET scan), or locoregionally advanced disease unsuitable for either surgical resection or radical chemoradiotherapy
4. Symptomatic dysphagia (Mellow score greater than 0)
5. ECOG performance status 0-2
6. Anticipated life expectancy of greater than 12 weeks.
7. Body weight of greater than 30kg.
8. Adequate bone marrow function, with values within the ranges specified below. Blood transfusions are permissible.

   1. White blood cell count greater than or equal to 2 x (10 to the power of 9)/L
   2. Absolute neutrophil count greater than or equal to 1.5 x (10 to the power of 9)/L
   3. Platelets greater than or equal to 100 x (10 to the power of 9)/L
   4. Haemoglobin greater than or equal to 90g/L
9. Adequate liver function, with values within the ranges specified below:

   1. Alanine transferase less than or equal to 2.5 x upper limit of normal (ULN)
   2. Aspartate transferase less than or equal to 2.5 x ULN
   3. Total bilirubin less than or equal to 1.5 x ULN (except patients with Gilbert's Syndrome, who can have total bilirubin less than or equal to 5 x ULN)
10. Adequate renal function, with values within the ranges specified below. Note that an estimated renal function of greater than 125mL/min by the Cockroft-Gault formula must not be used for carboplatin dosing, and must instead be determined using a direct method.

    1. Serum creatinine less than or equal to 1.5 x ULN
    2. Creatinine clearance (CrCl) greater than or equal to 40 mL/min using Cockroft-Gault formula
11. Tumour tissue (formalin-fixed, paraffin embedded) should be available for PD-L1 and mismatch repair (MMR) protein expression and can be provided as a block or slides (archival tissue is acceptable). Blocks prepared from cytological samples, where tumour cell number is sufficient, are also acceptable. Patients will not be selected by PD-L1 or MMR status.
12. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
13. Signed, written and informed consent.

Exclusion Criteria:

1. Bulky or organ-threatening metastatic disease requiring upfront higher dose chemotherapy in the judgement of the treating clinician.
2. Known tumour HER2 positivity (IHC 2+ or more and HER2 gene amplification on in situ hybridisation) if oligometastatic disease.
3. Previous systemic therapy for oesophageal or GOJ carcinoma.
4. Previous thoracic radiotherapy. Prior palliative radiotherapy to bony metastases is permitted.
5. Esophageal stent in situ.
6. Known tracheo-oesophageal fistula.
7. Known leptomeningeal or brain metastases.
8. Major surgical procedure (as defined by the Investigator) within 28 days prior to first day of study treatment. Note: Local surgery of isolated lesions for palliative intent is permitted.
9. History of another malignancy within the last 3 years, with the exception of adequately treated non-melanomatous skin cancer, carcinoma in situ and superficial transitional cell carcinoma of the bladder.
10. Prior therapy with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
11. Sensory neuropathy of grade 2 or higher severity per CTCAE v5.0.
12. History of allergy or hypersensitivity to study drug components, or other contraindications to any of the study drugs. Active or prior documented autoimmune disorders (including inflammatory bowel disease \[e.g., ulcerative colitis or Crohn's disease\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis\], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc). Patients with the following conditions are exceptions to this criterion:

    1. Vitiligo or alopecia.
    2. Hypothyroidism (e.g., following Hashimoto syndrome) stable on thyroid hormone replacement.
    3. Any chronic skin condition (e.g. psoriasis) that does not require systemic therapy.
    4. Type 1 diabetes mellitus.
    5. Coeliac disease controlled by diet alone.

    Patients without active autoimmune disease in the last 5 years may also be included but only after consultation with the Chief Principal Investigators.
13. Any condition requiring continuous systemic treatment with either regular corticosteroids (\>10mg daily prednisone or equivalent dose of an alternative corticosteroid) or other immunosuppressive medications within 14 days of study drug administration. Intranasal, inhaled or topical steroids, and adrenal replacement steroid doses \>10mg daily oral prednisone equivalent, are permitted in the absence of active autoimmune disease.
14. Positive test for hepatitis B surface antigen (HBsAg) indicating acute or chronic infection. Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HBsAg) are eligible.
15. Positive test for hepatitis C virus antibody (HCV antibody) , unless polymerase chain reaction is negative for HCV RNA.
16. History of other significant, or active, infection, including HIV or tuberculosis (TB). HIV testing is not mandatory unless clinically indicated. Clinical evaluation for active TB may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice.
17. Receipt of a transplanted solid organ (kidney, liver, heart or lung) or of an allogeneic bone marrow transplant.
18. Receipt of a live attenuated vaccine within 30 days prior to registration.
19. Use of alternative or traditional medicines within 14 days prior to registration.
20. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring adverse events or compromise the ability of the patient to give written informed consent.
21. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception to avoid pregnancy for 90 days after the last dose of durvalumab. Women of childbearing potential must have a negative pregnancy test within 24 hours prior to trial registration. Men must have been surgically sterilized or use a double barrier method of contraception if they are sexually active with a woman of childbearing potential for a period of 180 days after the last dose of durvalumab and chemotherapy, or 90 days after the last dose of durvalumab monotherapy (whichever is the longer time period). Sperm donation is not permitted for 180 days after the last dose of durvalumab and chemotherapy, or 90 days after the last dose of durvalumab monotherapy (whichever is the longer time period).

Primary outcomes:
measure: Progression free survival rate is the proportion of patients alive and progression free (the cancer has not worsened) assessed by CT scan and clinical review.
timeFrame: 6 months
Secondary outcomes:
measure: Duration of dysphagia relief
timeFrame: Mellow score will be assessed at days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until the end of treatment visits (30days after the last dose).
measure: Nutritional status
timeFrame: To be administered by a qualified dietician from date of randomisation until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 96 weeks.
measure: Quality of life change using the - European organisation for the research and treatment of cancer quality of life questionnaire QLQ-C30
timeFrame: Through study completion, an average of 1 year, using the 4-point ordinal scale - not at all, a little, quite a bit and very much
measure: Quality of life change using the - European organisation for the research and treatment of cancer quality of life questionnaire QLQ-OES18
timeFrame: Through study completion, an average of 1 year, using the 4-point ordinal scale - not at all, a little, quite a bit and very much
measure: Response rate in metastatic lesions
timeFrame: Assessment with imaging scans is performed at baseline then every 6 weeks while in treatment, then every 12 weeks until disease progression or date of death from any cause, whichever came first, assessed up to 96 weeks.
measure: Physician graded toxicity
timeFrame: Assessed from baseline to 90 days following last treatment dose.
measure: SAE Rate
timeFrame: Days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until to 100 days after last dose durvalumab regardless of relationship to drug.
measure: Overall survival.
timeFrame: Throughout study completion, average 2 years
Other outcomes:
Locations:
city: Albury
country: Australia
facility: Border Medical Oncology
state: New South Wales
city: Newcastle
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Grafton
country: New Zealand
facility: Auckland Hospital
state: Auckland
Study officials:
affiliation: Calvary Mater Newcastle
name: Fiona Day, Dr
role: STUDY_CHAIR
affiliation: Calvary Mater Newcastle
name: Jared Martin, Professor
role: STUDY_CHAIR
References: