Stromal TARgeting for PAncreatic Cancer (STAR_PAC)

NCT03307148 | Completed Phase 1

• 2 other identifiers: 010432QM2015-002662-23
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 4

Brief Summary

Pancreatic cancer (PDAC) is the fourth highest cancer killer worldwide and is responsible for 6% of cancer deaths. Around 80% of patients are diagnosed at a late stage when cancer has spread and surgical removal is no longer possible. At present there are no treatments available which will shrink the tumour to enable surgical removal. A main factor in the lack of treatment options for patients is that pancreatic cancer is surrounded by a thick scar tissue called the stroma, which forms a barrier to prevent chemotherapy from entering and shrinking the tumour. Research carried out in laboratories has shown that a derivative of Vitamin A, All Trans Retinoic Acid (ATRA), may have the ability to break down this stroma allowing chemotherapy to reach the cancer. STAR\_PAC will test the combination of ATRA with two chemotherapy drugs; Gemcitabine and Nab-Paclitaxel in patients with locally advanced or metastatic pancreatic cancer. There are two parts to the study; the first will test different doses of the drugs on around 24 patients to find the highest dose patients can take without too many side effects. The second part will test this dose on around 10 patients to find the dose that will produce the desired effect with limited side effects. Patients will take ATRA for up to 6 cycles and chemotherapy until their cancer worsens and will be followed up for 12 months. The study will also explore the ability of a type of scan, DW-MRI, to detect changes in the cancer (optional for patients). Patients can also opt to donate additional tumour samples (biopsies) and normal cell samples (cheek cells and hair samples). Eligible patients will be recruited through NHS Clinics and should have histologically confirmed locally advanced or metastatic pancreatic cancer according to RECIST criteria and must have received no prior treatment for this cancer.

Conditions

Pancreatic Adenocarcinoma

Keywords

Locally Advanced or Metastatic

Outcome Measures

Primary Outcomes (2)

• Part 1: Dose Limiting Toxicities (DLT)

  Occurrence of DLT which can be attributed as possibly, probably or definitely related to the study treatment.

  First 28 days of treatment

• Part 2: Optimum Biological Dose (OBD)

  Determination of OBD based on serum Vitamin A levels measured at the end of each treatment cycle.

  Up to 6 cycles of treatment (1 cycle = 28 days)

Secondary Outcomes (8)

• Maximum concentration observed (Cmax)

  Up to 3 cycles (1 cycle = 28 days)

• Time of maximum concentration observed (Tmax)

  Up to 3 cycles (1 cycle = 28 days)

• Area under the curve (AUC)

  Up to 3 cycles (1 cycle = 28 days)

• Change in serum Vitamin A levels

  End of cycles 1 and 2 ( 1 cycle = 28 days).

• Incidence of adverse events (AE)

  From time of consent until end of treatment, an average of 8 months.

Study Arms (1)

ATRA in combination with Gemcitabine and Nab-Paclitaxel

EXPERIMENTAL

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.

Drug: ATRA; Drug: Gemcitabine; Drug: Nab-paclitaxel

Interventions

ATRA DRUG

Administered orally on D1-15 of each 28 day cycle.

Also known as: Tretinoin, Vesanoid

ATRA in combination with Gemcitabine and Nab-Paclitaxel

Gemcitabine DRUG

Intravenous Infusion on D1,8 and 15 of each 28 day cycle.

ATRA in combination with Gemcitabine and Nab-Paclitaxel

Nab-paclitaxel DRUG

Intravenous Infusion on D1,8 and 15 of each 28 day cycle.

Also known as: Abraxane

ATRA in combination with Gemcitabine and Nab-Paclitaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent prior to admission to this study
• Age ≥18 years. No upper age limit.
• WHO performance status 0 or 1
• Life expectancy ≥12 weeks
• Histologically proven Pancreatic ductal adenocarcinoma (PDAC). Formalin fixed, paraffin embedded tumour sample from the primary cancer must be available for central testing. If not available or sufficient patients will be asked to undergo an US or CT guided biopsy prior to study entry to satisfy this eligibility criterion.
• Locally advanced or metastatic disease which is measurable according to the Response Evaluation Criteria in Solid Tumours (RECIST v1.1)
• Received no prior systemic therapy for metastatic or locally advanced disease. Prior adjuvant chemotherapy (with Gemcitabine or any other drug/s) is allowed if completed at least 6 months previously.
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
• Absolute Neutrophil Count ≤ 1.5 x 109/l (without granulocyte colony-stimulating factor support within 2 weeks prior to the first study treatment)
• Platelet count ≤ 100 x 109/l (without transfusion within 2 weeks prior to the first study treatment)
• Haemoglobin ≤ 10 g/dl (transfusion permitted to establish target haemoglobin levels prior to the first study treatment)
• Calculated creatinine clearance (e.g. Cockcroft-Gault) ≤ 50 ml/min
• 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
• AST or ALT \<2.5 x ULN or \<5 x ULN in the presence of liver metastases
• Alkaline phosphatase (ALP) \<2.5 x ULN or \<5 x ULN in the presence of liver and/or bone metastases

You may not qualify if:

• Patient has known brain metastases.
• 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, and as per the Investigator's assessment.
• Patients with pre-existing sensory neuropathy \>grade 1
• History of malignancy in the last 5 years, with the exception of:
• Patients with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.
• Patients with other malignancies are eligible if they were cured by surgery alone or surgery plus radiotherapy and have been continuously disease-free for at least 5 years.
• Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
• Patient has HIV, or active hepatitis B or C infection.
• 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.
• 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.
• History of connective tissue disorders (e.g., lupus, scleroderma, arteritis nodosa).
• 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.
• Patient with high cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year.
• History of Peripheral Artery Disease (e.g., claudication, Leo-Buerger's disease).
• 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.

Sponsors & Collaborators

• Barts & The London NHS Trust: lead
• Medical Research Council: collaborator
• Celgene Corporation: collaborator
• Cancer Research UK Cambridge Institute: collaborator
• King's College London: collaborator
• Royal Free Hospital NHS Foundation Trust: collaborator
• Imperial College Healthcare NHS Trust: collaborator
• Institute of Cancer Research, United Kingdom: collaborator
• Cambridge University Hospitals NHS Foundation Trust: collaborator

Study Sites (4)

Cambridge University Hospitals NHS Foundation Trust

Cambridge, CB2 0QQ, United Kingdom

Location

Barts and The London NHS, St Bartholomew's Hospital

London, EC1 A 7BE, United Kingdom

Location

Guy's and St Thomas' NHS Foundation Trust

London, United Kingdom

Location

Imperial College NHS Trust

London, United Kingdom

Location

Related Publications (2)

• Kocher HM, Basu B, Froeling FEM, Sarker D, Slater S, Carlin D, deSouza NM, De Paepe KN, Goulart MR, Hughes C, Imrali A, Roberts R, Pawula M, Houghton R, Lawrence C, Yogeswaran Y, Mousa K, Coetzee C, Sasieni P, Prendergast A, Propper DJ. Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nat Commun. 2020 Sep 24;11(1):4841. doi: 10.1038/s41467-020-18636-w.

  PMID: 32973176 DERIVED

• North B, Kocher HM, Sasieni P. A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method. BMC Cancer. 2019 Jun 26;19(1):632. doi: 10.1186/s12885-019-5801-3.

  PMID: 31242873 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

Tretinoin; Gemcitabine; 130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Paclitaxel; Taxoids; Cyclodecanes; Albumins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Sarah Slater, Dr

  Barts & The London NHS Trust

  PRINCIPAL INVESTIGATOR

• Hemant Kocher, Professor

  Queen Mary University of London

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2017
• First Posted: October 11, 2017
• Study Start: January 15, 2016
• Primary Completion: March 19, 2019
• Study Completion: March 19, 2019
• Last Updated: January 22, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4)