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Trial registered on ANZCTR


Registration number
ACTRN12619001371189
Ethics application status
Approved
Date submitted
10/09/2019
Date registered
8/10/2019
Date last updated
11/03/2020
Date data sharing statement initially provided
8/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial of palliative chemotherapy, Radiation and immune treatment for Oesophageal Cancer: PALEO Study
Scientific title
PALEO: A multicentre Phase II clinical trial examining progression free survival following treatment with palliative chemoradioimmunotherapy for metastatic oesophageal cancer
Secondary ID [1] 299190 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
PALEO Study
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Oesophageal Cancer 314291 0
Condition category
Condition code
Cancer 312642 312642 0 0
Oesophageal (gullet)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants with previously untreated oligometastatic oesophageal or gastro-oesophageal carcinoma and suffering from dysphagia will receive 2 weeks of therapy with concurrent hypofractionated radiotherapy (30Gy/10#) with weekly carboplatin (AUC 2) and paclitaxel (50 mg/m2) and nivolumab (240mg) intravenously every 2 weeks, followed by nivolumab (480mg) intravenously continuing at every 4 weeks until worsening of the cancer or up to a maximum of 24 months. In patients with one or more suitable metastases, a single metastasis will be treated with stereotactic radiotherapy (24Gy/3#) 4 weeks after the completion of the chemoradiotherapy to the oesophagus. Monitoring of adherence to treatment will be done by attendance at booked appointments.
Intervention code [1] 315486 0
Treatment: Drugs
Intervention code [2] 315487 0
Treatment: Other
Comparator / control treatment
No control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321294 0
Progression free survival rate is the proportion of patients alive and progression free (the cancer has not worsened) at 6 months assessed by CT Scan and clinical review.
Timepoint [1] 321294 0
The interval from the date of participant registration to the date of a progression free survival event:
1. date of the first CT scan to show disease progression
2. patient is judged to have progressed by the responsible investigator (in the event that no RECIST assessment is available)
3.death occurs.

Patients will be followed up indefinitely until they experience one of the pre-defined progression free survival events listed above.
Secondary outcome [1] 374545 0
dysphagia using Mellow score
Timepoint [1] 374545 0
Mellow score will be assessed at days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until the end of treatment visit. During the follow up period the mellow score will be measured every six weeks until week 25 of the followup period and then every 12 weeks indefinitely until progressive disease. If a patient discontinues treatment due to progressive disease the Mellow score will only be recorded at the end of treatment visit.

Mellow score may be optionally assessed at days 22, 36 and 50 if the participants attends the clinic for any other unscheduled visit.
Secondary outcome [2] 374546 0
Maximum improvement in dysphagia assessed using the Mellow score,
Timepoint [2] 374546 0
Best score improvement (at any time as assessed at the following time points: days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until the end of treatment visit. During the follow up period the mellow score will be measured every six weeks until week 25 of the followup period and then every 12 weeks indefinitely until progressive disease. If a patient discontinues treatment due to progressive disease the Mellow score will only be recorded at the end of treatment visit.
Mellow score may be optionally assessed at days 22, 36 and 50 if the participants attends the clinic for any other unscheduled visit.)
Secondary outcome [3] 374547 0
Nutritional status change as determined by cessation of baseline enteral feeding (where relevant). this will be collected from the participant using the scored Patient-generated subjective global assessment (PG_SGA) tool and clinical review,
Timepoint [3] 374547 0

Days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until treatment cycle 8 when it will be assessed every 12 weeks until the end of treatment.

It may be optionally assessed at days 22, 36 and 50 if the participants attends the clinic for any other unscheduled visit.
Secondary outcome [4] 374548 0
Quality of life change over 12 weeks using the EORTC QLQ-C30 and
Timepoint [4] 374548 0
Day 1, 29,43,85, 127, 169 and 253 and every 12 weeks thereafter until the final assessment at the end of treatment visit.
Secondary outcome [5] 374549 0
Response rate in metastatic lesions is assessed using radiological imaging with Contrast Cat Scan (chest and abdomen, + neck)
Timepoint [5] 374549 0
Best response (at any time). Assessment with imaging scans is anchored to cycle 1 day 1 treatment and should be performed in the week prior to scheduled clinic visits at Week 6, Week 12, Week 18, Week 24 then every 12 weeks indefinitely until disease progression.

Disease progression is to be confirmed by iRECIST (Immunotherapy Response Evaluation Criteria in Solid Tumors) at least 4 weeks after iUPD (immunotherapy unconfirmed progressive disease) finding
Secondary outcome [6] 374550 0
Physician graded toxicity (CTCAE v5.0)
Timepoint [6] 374550 0
Highest toxicity (at any time) assessed at the following time points: days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter. Toxicity will also be assessed at end of treatment visit, the safety follow up visit (13 weeks after the end of treatment visit) and if the participant has not experienced progressive disease then every 6 weeks until week 25 follow up visit and the every 12 weeks indefinitely until progressive disease.

Toxicity may be optionally assessed at days 22, 36 and 50 if the participants attends the clinic or any other unscheduled visit.
Secondary outcome [7] 374551 0
SAE Rate will be assessed as reported by the participant and by clinician assessment from consent signing to 100 days after last dose nivolumab regardless of relationship to drug. Adverse events will be documented in the patient medical record.
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
1) results in death,
2) is life-threatening (i.e. the participant is at risk of death at the time of the event),
3) requires inpatient hospitalisation or prolongation of existing hospitalisation,
4) results in persistent or significant disability or incapacity,
5) is a congenital anomaly/birth defect,
6) other important medical events which may jeopardize the patient or may require intervention to prevent one of the listed outcomes in the definition above, which, in the opinion of the Investigator, are likely to become serious if untreated.
Timepoint [7] 374551 0
Highest toxicity (at any time) assessed at the following time points: days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until to 100 days after last dose nivolumab regardless of relationship to drug. Toxicity may be optionally assessed at days 22, 36 and 50 if the participants attends the clinic or any other unscheduled visit.
Secondary outcome [8] 374553 0
Overall survival.
Overall survival is defined as the interval from the date of patient registration to date of death from any cause, or the date last known alive.
Timepoint [8] 374553 0
Overall survival will be reported with Kaplan Meier curves and summarized by their medians, and proportions event-free at 1 year.
Survival will be assessed at scheduled visits at the following time points days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until the end of treatment visit. survival will then be assessed at week 13 following end of treatment visit. For participants who have not experienced progressive disease survival follow will be assessed every 6 weeks until week 25 follow up visit and the every 12 weeks indefinitely until progressive disease. Following progressive disease participants will be monitored for survival every 12 weeks indefinitely until death.

Survival optionally assessed at days 22, 36 and 50 if the participants attends the clinic or any other unscheduled visit.

Contact by phone or medical record review acceptable if patient does not attend any scheduled visit.
Secondary outcome [9] 374554 0
Exploratory endpoints: Immune translational studies. The type of Immune translational studies cannot be described at this time however prospective tumour tissue and blood are being collected from participants with consent for these future translational studies.
Timepoint [9] 374554 0
Translational bloods samples will be collected at the following time points: day 1, 29, 57, 85 and at end of treatment (within 30 days of last dose of nivolumab)
Archival formalin-fixed, paraffin embedded tumour tissue ill be obtained with the participants consent and held for future translational studies.
Secondary outcome [10] 375013 0
Nutritional status change as determined by Patient weight
Timepoint [10] 375013 0
Days 1, 8, 15, 29, 43, 57 and then every 4 weeks thereafter until treatment cycle 8 when it will be assessed every 12 weeks until the end of treatment. .

Weight may be optionally assessed at days 22, 36 and 50 if the participants attends the clinic for any other unscheduled visit.
Secondary outcome [11] 375014 0
Nutritional status change as determined by Patient Generated Subjective Global Assessment (PG-SGA)
Timepoint [11] 375014 0
Days 1, 29, 85, 127, 169, 253 and then every 12 weeks thereafter until the end of treatment.
Secondary outcome [12] 375015 0
Quality of life change over 12 weeks assessed by using the QLQ-OES18
Timepoint [12] 375015 0
Days 1, 29, 85, 127, 169, 253 and then every 12 weeks thereafter indefinitely until disease progression.

Eligibility
Key inclusion criteria
1. Males and females > 18 years of age.
2. Biopsy proven carcinoma of the oesophagus or gastro-oesophageal junction
3. Oligometastatic disease (1-5 lesions outside the primary tumour radiotherapy field on FDG-PET)
4. Symptomatic dysphagia (Mellow score >0)
5. ECOG performance status 0-1
6. Adequate bone marrow function, with values within the ranges specified below. Blood transfusions are permissible.
a. White blood cell count equal to or greater than 2 x 109/L
b. Absolute neutrophil count equal to or greater than 1.5 x 109/L
c. Platelets equal to or greater than 100 x 109/L
d. Haemoglobin equal to or greater than 90g/L
7. Adequate liver function, with values within the ranges specified below:
a. Alanine transferase equal to or less than 3 x upper limit of normal (ULN)
b. Aspartate transferase equal to or less than 3 x ULN
c. Total bilirubin equal to or less than 1.5 x ULN (except patients with Gilbert’s Syndrome, who can have total bilirubin equal to or greater than 5 x ULN)
8. Adequate renal function, with values within the ranges specified below. Note that an estimated renal function of >125mL/min by the Cockroft-Gault formula must not be used for carboplatin dosing, and must instead be determined using a direct method.
a. Serum creatinine equal to or less than 1.5 x ULN
b. Creatinine clearance (CrCl) equal to or greater than 40 mL/min using Cockroft-Gault formula
9. 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.
10. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
11. Signed, written and informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Bulky or organ-threatening metastatic disease requiring 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)
3. Previous systemic therapy for oesophageal or GOJ carcinoma
4. Previous thoracic radiotherapy
5. Oesophageal stent in situ
6. Known tracheo-oesophageal fistula.
7. Leptomeningeal or uncontrolled brain metastases. Controlled brain metastases are those which have been treated and are radiologically and/or clinically stable, and the patient is asymptomatic and does not require steroids.
8. Life expectancy of less than 6 months.
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.
13. Active, known or suspected autoimmune disease. Patients are not excluded if they have vitiligo, type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of a trigger.
14. Any condition requiring 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 are permitted in the absence of active autoimmune disease.
15. Positive test for hepatitis B surface antigen (HBsAg) or antibodies to hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
16. History of other significant, or active, infection, including HIV. HIV testing is not mandatory unless clinically indicated.
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. Pre-existing medical condition that in the opinion of the investigator would increase the risk associated with study participation or interfere with the interpretation of safety results.
21. Serious medical or psychiatric conditions which may limit the ability of the patient to comply with the clinical trial protocol.
22. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception to avoid pregnancy for 23 weeks after the last dose of nivolumab. 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 31 weeks after the last dose of nivolumab. Sperm donation is not permitted for a period of 31 weeks after the last dose of nivolumab.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Nil
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary measure of effect for this trial is the progression free survival rate at 6 months. The 6 month PFS rate and its 95% confidence interval will be determined using the Kaplan Meier method.
The secondary outcome measures of progression free survival and overall survival will be reported with Kaplan Meier curves and summarized by their medians, and proportions event-free at 1 year. The objective tumour response rate will be reported as binomial proportions on the evaluable patient subgroup with 95% confidence intervals.
Analyses of safety endpoints will include all patients who received at least one radiotherapy fraction and/or one dose of carboplatin, paclitaxel or nivolumab. Reporting of safety endpoints will include summaries of adverse events experienced whilst on treatment and to 100 days after the last nivolumab dose, and their grades.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 14722 0
Calvary Mater Newcastle - Waratah
Recruitment postcode(s) [1] 27762 0
2298 - Waratah

Funding & Sponsors
Funding source category [1] 303729 0
Hospital
Name [1] 303729 0
Calvary Mater Newcastle
Address [1] 303729 0
Edith Street Waratah NSW 2298
Country [1] 303729 0
Australia
Primary sponsor type
Hospital
Name
Calvary Mater Newcastle
Address
Edith Street Waratah NSW 2298
Country
Australia
Secondary sponsor category [1] 303864 0
None
Name [1] 303864 0
Address [1] 303864 0
Country [1] 303864 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304254 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 304254 0
Research Ethics and Governance Office
The Lodge, Rankin Park Campus
Lookout Road,
New Lambton NSW 2305
Ethics committee country [1] 304254 0
Australia
Date submitted for ethics approval [1] 304254 0
26/08/2019
Approval date [1] 304254 0
02/09/2019
Ethics approval number [1] 304254 0
2019/ETH12056

Summary
Brief summary
The purpose of this study is to investigate the effects of the addition of the stereotactic body radiotherapy and nivolumab to a well tolerated 2 week chemotherapy and radiation treatment regimen in people with oesophageal cancer that has spread to another are of the body (metastasised).

Who is it for?

You may be eligible for this study if you are an adult who has cancer of the oesophagus or gastro-oesophageal junction that has spread to other parts of your body.

Study details

All participants in this study will receive 10 treatments of radiotherapy to the primary oesophageal 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. Nivolumab, an immune therapy, received intravenously; will be given every two weeks from the beginning of radiation therapy for eight weeks.

After this participants will continue to receive immune therapy (nivolumab), 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 through out 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). Cat 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 through out 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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 96302 0
Dr Fiona Day
Address 96302 0
Calvary Mater Newcastle Edith Street Waratah NSW 2298
Country 96302 0
Australia
Phone 96302 0
+61 240143564
Fax 96302 0
61240143557
Email 96302 0
fiona.day@calvarymater.org.au
Contact person for public queries
Name 96303 0
Dr Fiona Day
Address 96303 0
Calvary Mater Newcastle Edith Street Waratah NSW 2298
Country 96303 0
Australia
Phone 96303 0
+61 240143285
Fax 96303 0
61240143287
Email 96303 0
PALEO@calvarymater.org.au
Contact person for scientific queries
Name 96304 0
Dr Fiona Day
Address 96304 0
Calvary Mater Newcastle Edith Street Waratah NSW 2298
Country 96304 0
Australia
Phone 96304 0
+61 240143564
Fax 96304 0
61240143557
Email 96304 0
PALEO@calvarymater.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data sharing is encouraged and will be considered following submission of a concept for a secondary analysis
What supporting documents are/will be available?
Ethical approval
How or where can supporting documents be obtained?
Type [1] 4592 0
Ethical approval
Citation [1] 4592 0
Link [1] 4592 0
Email [1] 4592 0
Other [1] 4592 0
Summary results
No Results