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A Randomised Trial of ATRA in a Novel Drug Combination for Pancreatic Cancer (STARPAC2)

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ClinicalTrials.gov Identifier: NCT04241276
Recruitment Status : Active, not recruiting
First Posted : January 27, 2020
Last Update Posted : June 6, 2024
Sponsor:
Collaborators:
Medical Research Council
Celgene
Information provided by (Responsible Party):
Queen Mary University of London

Tracking Information
First Submitted Date  ICMJE January 22, 2020
First Posted Date  ICMJE January 27, 2020
Last Update Posted Date June 6, 2024
Actual Study Start Date  ICMJE April 30, 2020
Estimated Primary Completion Date November 30, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 3, 2024)
To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on progression free survival (PFS). [ Time Frame: Assessed 8 weekly until progression or death or end of trial, whichever comes first ]
PFS defined as the time from the date of randomisation to the date of first documented tumour progression or death from any cause, whichever occurs first.
Original Primary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on progression free survival (PFS). [ Time Frame: Assessed 8 weekly until progression or death ]
PFS defined as the time from the date of randomisation to the date of first documented tumour progression or death from any cause, whichever occurs first.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2024)
  • To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on objective response rate (ORR). [ Time Frame: Assessed 8 weekly until progression or death or end of trial, whichever comes first ]
    ORR defined as the number of patients with an objective response (OR) divided by the number of patients analysed. OR is defined as the number of patients with at least one confirmed response of complete response (CR) or partial response (PR). OR will be calculated in patients with measurable disease at baseline.
  • To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on overall survival (OS). [ Time Frame: Assessed 8 weekly until progression or death and then 3 monthly for at least 12 months after the last safety visit ]
    OS is defined as the time from the date of randomisation to death from any cause.
  • To assess the safety and tolerability of ATRA when given in combination with gemcitabine and nab-paclitaxel over the first 6 cycles. [ Time Frame: 6 cycles (1 cycle = 28 days) ]
    The worst recorded toxicity grade for each patient on the NCI-CTCAE toxicity scale (version 5.0) over the first 6 cycles of treatment
  • To assess the surgical resection rate of ATRA when given in combination with gemcitabine and nab-paclitaxel. [ Time Frame: From consent to at least 12 months after the last safety visit, but further if required as per physician decision - through study completion ]
    Surgical resection rate defined as patients undergoing complete resection of known pancreatic primary and associated lymph nodes at any point after enrolment, in each arm.
  • To assess the resection margin negative (R0) surgical resection rate of ATRA when given in combination with gemcitabine and nab-paclitaxel. [ Time Frame: From consent to at least 12 months after the last safety visit, but further if required as per physician decision - through study completion ]
    R0 surgical resection rate defined as histologically confirmed complete resection of known pancreatic primary from those resected.
  • To assess quality of life (QOL) of patients receiving ATRA in combination with Gemcitabine and Nab-Paclitaxel: EQ-5D-5L [ Time Frame: Assessed at the beginning of each cycle until progression (1 cycle = 28 days) ]
    QoL scores for the five dimensions of the EQ-5D-5L (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) will be used to calculate weighted health status scores.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2020)
  • To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on objective response rate (ORR). [ Time Frame: Assessed 8 weekly until progression or death ]
    ORR defined as the number of patients with an objective response (OR) divided by the number of patients analysed. OR is defined as the number of patients with at least one confirmed response of complete response (CR) or partial response (PR). OR will be calculated in patients with measurable disease at baseline.
  • To assess the efficacy of ATRA when given in combination with gemcitabine and nab-paclitaxel based on overall survival (OS). [ Time Frame: Assessed 8 weekly until progression or death and then 3 monthly for at least 12 months after the last safety visit ]
    OS is defined as the time from the date of randomisation to death from any cause.
  • To assess the safety and tolerability of ATRA when given in combination with gemcitabine and nab-paclitaxel over the first 6 cycles. [ Time Frame: 6 cycles (1 cycle = 28 days) ]
    Safety and tolerability as assessed by AEs (CTCAE v5.0).
  • To assess the surgical resection rate of ATRA when given in combination with gemcitabine and nab-paclitaxel. [ Time Frame: From consent to at least 12 months after the last safety visit, but further if required as per physician decision. ]
    Surgical resection rate defined as patients undergoing complete resection of known pancreatic primary and associated lymph nodes at any point after enrolment, in each arm.
  • To assess the resection margin negative (R0) surgical resection rate of ATRA when given in combination with gemcitabine and nab-paclitaxel. [ Time Frame: From consent to at least 12 months after the last safety visit, but further if required as per physician decision. ]
    R0 surgical resection rate defined as histologically confirmed complete resection of known pancreatic primary from those resected.
  • To assess quality of life (QOL) of patients receiving ATRA in combination with Gemcitabine and Nab-Paclitaxel: EQ-5D-5L [ Time Frame: Assessed at the beginning of each cycle until progression (1 cycle = 28 days) ]
    Patient reported outcomes as measured by questionnaire EQ-5D-5L
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Randomised Trial of ATRA in a Novel Drug Combination for Pancreatic Cancer
Official Title  ICMJE Phase IIb Randomised Clinical Trial Repurposing ATRA as a Stromal Targeting Agent in a Novel Drug Combination for Pancreatic Cancer
Brief Summary This is an open-label, multi-centre, randomised, stratified, phase IIb clinical trial of ATRA administered in combination with gemcitabine and nab-paclitaxel in patients with laPDAC.
Detailed Description Patients will be randomised to receive gemcitabine + nab-paclitaxel or gemcitabine + nab-paclitaxel + ATRA. Treatment will be administered in 28 day cycles. ATRA will be administered for 6 cycles whereas gemcitabine/nab-paclitaxel will be administered until disease progression. Treatment may be discontinued earlier due to unacceptable toxicities or death or because the patient requests to be withdrawn from study treatment. If treatment with gemcitabine/nab-paclitaxel is stopped prior to the patient completing 6 cycles of treatment with ATRA (if allocated), the patient may continue on treatment with ATRA alone until the 6 cycles are completed, at the discretion of the treating physician.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pancreatic Cancer
Intervention  ICMJE
  • Drug: ATRA
    45 mg/m2 orally (in two divided doses) from days 1 to 15 of each cycle
    Other Names:
    • Tretinoin
    • Vesanoid
  • Drug: Gemcitabine
    1000mg/m2 IV on days 1, 8 and 15 of a 28 day cycle
  • Drug: nab-paclitaxel
    125mg/m2 IV on days 1, 8 and 15 of a 28 day cycle
    Other Name: Abraxane
Study Arms  ICMJE
  • Active Comparator: Gemcitabine + nab-paclitaxel
    Patients will receive Gemcitabine and nab-Paclitaxel in 28 day cycles until disease progression.
    Interventions:
    • Drug: Gemcitabine
    • Drug: nab-paclitaxel
  • Experimental: Gemcitabine + nab-paclitaxel + ATRA
    Patients will receive ATRA, Gemcitabine and nab-Paclitaxel in 28 day cycles. ATRA will be administered for 6 cycles whereas Gemcitabine/nab-Paclitaxel will be administered until disease progression.
    Interventions:
    • Drug: ATRA
    • Drug: Gemcitabine
    • Drug: nab-paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2020)
170
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 29, 2025
Estimated Primary Completion Date November 30, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

  1. Written informed consent prior to admission to this study
  2. Age ≥16 years. No upper age limit.
  3. ECOG performance status 0 or 1
  4. Histologically proven pancreatic ductal adenocarcinoma (PDAC) as part of the Precision-Panc Master Protocol, or for patients who have gone exploratory laparotomy and found to have locally, unresectable advanced disease.
  5. Locally advanced disease which is measurable according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1).
  6. CT chest abdomen and pelvis as well as PET-CT within 28 days of day 1 of treatment (MRI Liver only if indeterminate liver lesions) to confirm absence of metastatic disease.
  7. Received no prior systemic therapy for pancreatic cancer.
  8. Adequate haematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:

    1. Absolute Neutrophil Count ≥ 1.5 x 109/l (without granulocyte colony-stimulating factor support within 2 weeks prior to the first study treatment)
    2. Platelet count ≥ 100 x 109/l (without transfusion within 2 weeks prior to the first study treatment)
    3. Haemoglobin ≥ 10 g/dl (transfusion permitted to establish target haemoglobin levels prior to the first study treatment)
    4. Calculated creatinine clearance (e.g. Cockcroft-Gault) ≥ 50 ml/min
    5. Bilirubin level ≤ 1.5 ULN (patients with known Gilbert disease who have bilirubin levels ≤ 3 x ULN may be enrolled). Patients must be able to undergo biliary stenting if required before or, if required, during the trial
    6. AST or ALT <2.5 x ULN
    7. Alkaline phosphatase (ALP) <2.5 x ULN
    8. INR and aPTT ≤1.5 x ULN; this applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
  9. Female patients of child-bearing potential are eligible, provided they have a negative serum pregnancy test within 7 days prior to the first dose of study treatment, preferably as close to the first dose as possible. All patients with reproductive potential must agree to use a medically acceptable method of contraception throughout the treatment period and for 1 month after discontinuation of ATRA and / or gemcitabine/nab-paclitaxel (whichever is the latest) and for 6 months after discontinuation for male patients. Acceptable methods of contraception include IUD, oral contraceptive, sub-dermal implant and double barrier (condom with a contraceptive sponge or contraceptive pessary). Micro-dosed progesterone preparations ("mini-pill") are an inadequate method of contraception during treatment with ATRA. If patients are taking this pill they should be instructed to stop and another form of contraceptive should be prescribed instead.
  10. Able to follow protocol requirements as assessed by the Principal Investigator.

Exclusion Criteria:

A patient will not be eligible for inclusion in this study if any of the following criteria apply:

  1. Patient has known distant metastases.
  2. Patient has experienced a significant reduction in performance status between the screening/ baseline visit and within 72 hours prior to commencement of treatment as per trial protocol, such that the ECOG PS is ≥ 2 as per the Investigator's assessment.
  3. Patients with pre-existing sensory neuropathy >grade 1
  4. History of other malignancies (except cured basal or squamous cell carcinoma, superficial bladder cancer, prostate cancer in active surveillance, or carcinoma in situ of the cervix) unless documented free of cancer for ≥2 years
  5. Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
  6. Patient has known active, uncontrolled HIV, or active, uncontrolled hepatitis B or C infection. Patients with undetectable viral load are eligible.
  7. Patient has undergone major surgery, other than diagnostic surgery (i.e., surgery done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks prior to Day 1 of treatment in this study.
  8. Patient has a history of allergy (including soya bean or peanut allergies) or hypersensitivity to any of the study drugs or any of their excipients, or the patient exhibits any of the events outlined in the Contraindications or Special Warnings and Precautions sections of the products or comparator SmPC or Prescribing Information.
  9. History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa).
  10. Patient with a history of interstitial lung disease, history of slowly progressive dyspnoea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.
  11. Patient with high cardiovascular risk , including, but not limited to, recent coronary stenting or myocardial infarction in the past year.
  12. History of Peripheral Artery Disease (e.g., claudication, Leo-Buerger's disease).
  13. Patient has serious medical risk factors involving any of the major organ systems, or serious psychiatric disorders, which could compromise the patient's safety or the study data integrity.
  14. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug at least ≤30 days prior to study entry depending on the half-life of the investigational drug and/or guidance issued by the IMP manufacturer.
  15. Patient is taking any prohibited concurrent medication, including vitamin A supplements, and is unwilling to stop use prior to and during the trial.
  16. Patient is pregnant, planning to become pregnant or breast feeding.
  17. Patient has received a live vaccine within four weeks prior to receiving their first dose of study treatment.
  18. Patient is unwilling or unable to comply with study procedures, as assessed by the Principal Investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04241276
Other Study ID Numbers  ICMJE 274948
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Current Responsible Party Queen Mary University of London
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Queen Mary University of London
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Medical Research Council
  • Celgene
Investigators  ICMJE
Study Chair: Hemant Kocher, Professor Queen Mary University of London
PRS Account Queen Mary University of London
Verification Date June 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP