Acelarin First Line Randomised Pancreatic Study
Acelarin First Line Randomised Pancreatic Study
The primary purpose of this study is to assess whether Acelarin (NUC-1031) is superior to
 gemcitabine in terms of overall survival for treatment of patients with metastatic pancreatic
 carcinoma. In addition disease progression, quality of life and comparative safety will be
 evaluated. Secondary objectives are to compare between the two treatment groups the
 following:

 -  Progression Free Survival (PFS)

 -  Radiological Response and disease control rate

 -  Toxicity and safety

 -  Quality of Life

 Additional, exploratory objectives are to discover and validate possible biomarkers to
 predict additional benefit of Acelarin (NUC-1031) over gemcitabine alone.
Pancreatic cancer remains the most lethal of solid tumours with little progress being made to
 improve patient outcomes over the past 30 years of research. The incidence in the UK is
 approximately 9,000 new cases per year and, with a 5 year survival remaining at just 3%,
 mortality approximates incidence. These dismal outcomes reflect:

 1. Advanced stage at presentation such that only a minority of patients are suitable for
 surgery with curative intent;

 2. High rates of recurrence even in those undergoing radical surgery;

 3. Limited efficacy of systemic therapies.

 Until recently, the mainstay of systemic therapy for advanced pancreatic cancer was
 gemcitabine, based on the pivotal study in 1997 by Burris et al., reporting a survival
 and clinical benefit when compared with 5-FU. However, this benefit is modest with
 median and 1-year survival of approximately 6 months and 20% respectively for patients
 with metastatic disease. Combination chemotherapy has shown more promising results but
 at the expense of significant toxicity limiting this to younger patients with good
 performance status.

 Although these chemotherapy combinations confer a survival advantage over gemcitabine,
 their use is restricted to a cohort of patients able, and willing, to tolerate
 additional toxicity. Pancreatic cancer is commonly associated with:

 (i) increasing age; (ii) co-morbidities (for example, diabetes mellitus which, if
 associated with peripheral neuropathy, may limit the safe administration of neurotoxic
 drugs such as oxaliplatin and nab-paclitaxel); (iii) symptoms that negatively impact on
 performance status; (iv) biliary obstruction requiring stenting, with associated risks
 of sepsis and impaired drug metabolism.

 Thus, for a large proportion of patients single agent gemcitabine remains an appropriate
 standard chemotherapy. For this group of patients, more efficacious and better tolerated
 treatment is required.

 The study is being performed to investigate whether Acelarin provides improvement in
 overall survival compared with gemcitabine. This is a pivotal study in this indication
 and will represent the landmark data for whether there is additional benefit from
 Acelarin in pancreatic cancer.

 Gemcitabine monotherapy, the control arm, remains a standard of care in this disease.
 The only treatments that have shown improved outcome over gemcitabine are Folfirinox and
 nab-paclitaxel in combination with gemcitabine. However, the application of these
 regimens to a large proportion of patients with pancreatic cancer is limited by the
 potential for significant toxicities.

 Acelarin (NUC-1031) is a first-in-class nucleotide analogue, which uses novel
 phosphoramidate technology to overcome the key cancer resistance mechanisms associated
 with gemcitabine.

 Acelarin is synthesised as a pre-activated molecule bearing one protected phosphate
 group, termed the phosphoramidate motif, imparting several potential advantages to this
 new agent over gemcitabine:

 -  Acelarin (NUC-1031) overcomes the reliance on nucleoside transporters to cross the
 cellular membrane for effective uptake by the cancer cells.

 -  Acelarin (NUC-1031) presents the cell with an already partially activated
 (monophosphate) form of the nucleoside, thereby obviating the need for the rate
 limiting initial kinase activation.

 -  Acelarin (NUC-1031) is protected from enzymatic breakdown (especially by deaminases
 and phosphorylases) resulting in greater stability and a reduction in the
 generation of toxic metabolites.

 The clinical relevance of these resistance mechanisms has been well documented.

 Multiple active nucleoside transporters located in the cell membrane carry out the
 transport of nucleoside analogues, such as gemcitabine, into the cells. The human
 equilibrative nucleoside transporter, hENT1 mediates the majority of gemcitabine uptake.
 It is therefore expected that hENT1-deficient cells are highly resistant to gemcitabine
 (Achiwa et al., Cancer Sci. 2004).

 Nucleoside transport deficiency is an important predictive factor for gemcitabine
 response in patients with cancer. Spratlin et al.,demonstrated that the presence of
 nucleoside transporters correlated with improved response to gemcitabine and OS in
 patients with pancreatic cancer (Spratlin et al Clin Cancer Res. 2004). Patients
 expressing hENT1 had a median survival of 13 months compared to only 4 months in
 patients with little or no hENT1 activity.

 Acelarin has been shown to overcome the need for hENT1 active transport to enter the
 cancer cells. The greater lipophilicity allows Acelarin to cross the cell membrane
 independently of nucleoside transporters.

 To become active, nucleoside analogues require sequential steps of phosphorylation
 within the cancer cells. Deficiency in dCK is a frequently described form of in-vitro
 and in-vivo inherent as well as acquired resistance to gemcitabine. Acelarin is
 synthesised as a monophosphate agent and, as such, has by-passed the rate limiting step
 of kinase-dependent activation.

 Acelarin bears a phosphoramidate moiety on the ribose 5' carbon, which protects the
 compound from deamination (Slusarczyk et al J Med Chem 2014) , which may confer
 considerable survival advantages and a more favourable safety profile (Ghazali et al JCO
 322:5s, 2014).

 It is planned to perform this study in approximately 40 UK centres with additional
 centres in Europe and the USA with a centre defined as the primary institution of the
 clinical investigator. Recruitment will be competitive and 328 patients will be
 randomised in a 1:1 fashion.

 Randomisation will be stratified by ECOG performance status (PS) (0/1 vs 2).

 Baseline radiographic assessment of disease will be performed within 28 days prior to
 first treatment and first treatment will be delivered within 8 days of randomisation or
 the earliest screening procedure, e.g. blood samples, CT scan whichever is sooner as
 follows:

 Arm A (experimental arm): Acelarin (NUC-1031)

 Acelarin: 825 mg/m2 administered intravenously over 15 to 30 minutes on days 1, 8 and 15
 of a 28 day cycle

 Arm B (standard therapeutic arm): Gemcitabine

 Gemcitabine: 1000mg/m2 administered intravenously as a 30 minute infusion on days 1, 8
 and 15 of a 28 day cycle

 Patients will be seen on a weekly basis during the time they are on active treatment and
 will be treated until disease progression. At the completion of therapy, an end-of
 therapy visit must be completed within 7 days after the decision is made to discontinue
 all therapy. This must be a full assessment consisting of physical exam, Performance
 Status, ECG, haematology and chemistry profile and toxicity/AE assessments, after which
 follow up will then occur every 12 weeks. CT scans of the chest, abdomen and pelvis will
 take place at screening then every 12 weeks thereafter until disease progression as per
 RECIST 1.1.

 No further anti-tumour treatment will be initiated until progression of disease. AE
 information will be collected until at least 30 days after the last dose of study
 therapy is administered or until all study therapy-related AEs have resolved, stabilised
 or been deemed irreversible and a 30 day safety follow up should be performed at this
 point.

 A phase I/II clinical study has established the RP2D and schedule for Acelarin as 825
 mg/m2 administered intravenously on days 1, 8 and 15 of a 28 day cycle. Two dose
 limiting toxicities were observed (grade 3 transaminitis at 725mg/m2 and grade 4
 thrombocytopenia at 750mg/m2). Otherwise treatment was well-tolerated with no unexpected
 adverse events. Adverse events were generally mild to moderate with the most common
 grade 1 and 2 AEs being anaemia, fatigue, transaminitis and thrombocytopenia. Only three
 patients experienced grade 4 AEs: thrombocytopenia, hypomagnesaemia and sepsis.

 The following precautionary measures will also be put in place:

 -  Assessment of full blood count, renal function and liver function will be made
 prior to each administration of Acelarin.

 -  The occurrence of haematological toxicity including neutropenia and
 thrombocytopenia which requires dose adjustment is specified in the protocol.

 -  The effect of renal impairment on exposure to Acelarin in patients with renal
 impairment is not known. Therefore study entry is restricted to patients with
 creatinine clearance ≥ 30mL/minute.

 -  Acelarin should not be administered to pregnant women. A negative pregnancy test
 should be confirmed before administration of Acelarin for all women of childbearing
 age.

 -  There is no known antidote for Acelarin, and treatment of AEs associated with its
 use should be for the underlying adverse symptoms.

 -  Since Acelarin will be reconstituted in specialist oncology pharmacies and
 administered by experienced chemotherapy-trained nurses via intravenous injection,
 overdose is considered to be highly unlikely. There is no specific treatment for an
 overdose of Acelarin. In case of overdose, therapy may be interrupted, and any
 adverse reactions treated symptomatically.

 Assessment of full blood count, renal function and liver function will be made prior to
 each administration of gemcitabine.

 The occurrence of haematological toxicity including neutropenia and thrombocytopenia
 which requires dose adjustment is specified in the protocol.
Inclusion Criteria:

 -  Age ≥ 18 years.

 -  Histologically or cytologically proven pancreatic ductal adenocarcinoma or
 undifferentiated carcinoma of the pancreas.

 -  Metastatic disease precluding curative surgical resection or definitive locally
 directed therapies such as chemo radiation. Patients who have relapsed following
 previously resected pancreatic cancer can be included.

 -  Contrast enhanced computerised tomography (CT) scan of the thorax, abdomen and pelvis
 within 28 days prior to commencing treatment.

 -  Unidimensionally measurable disease.

 -  ECOG performance status 0, 1 or 2 where combination chemotherapy is not deemed
 appropriate or is declined by the patient.

 -  Platelets ≥100 x 109/l; WBC ≥ 3 x 109/l; neutrophils ≥ 1.5 x 109/l at entry.

 -  Documented life expectancy > 3 months.

 -  Informed written consent.

 Exclusion Criteria:

 -  Laboratory results:

 -  Serum bilirubin ≥ 1.5x the upper limit of reference range (ULRR).

 -  Haemoglobin < 10G/dl.

 -  Creatinine clearance < 30 mL/minute (calculated by Cockcroft-Gault formula).

 -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 x ULN or
 > 5x ULN if judged by the investigator to be related to liver metastases.

 -  Medical or psychiatric conditions compromising informed consent.

 -  Intracerebral metastases or meningeal carcinomatosis.

 -  Evidence of severe or uncontrolled systemic disease or any concurrent condition which
 in the Investigator's opinion makes it undesirable for the patient to participate in
 the study or which would jeopardize compliance with the protocol.

 -  Pregnancy or breast feeding.

 -  Previous chemotherapy for locally advanced and metastatic disease. Adjuvant
 chemotherapy for resected pancreatic cancer will be permitted provided that
 chemotherapy was completed > 12 months previously.

 -  Radiotherapy within the last 4 weeks prior to start of study treatment.

 -  Concurrent malignancies or invasive cancers diagnosed within past 5 years except for
 adequately treated basal cell carcinoma of the skin, in situ carcinoma of the uterine
 cervix or resected pancreatic cancer.

 -  Hypersensitivity to gemcitabine or any of the excipients of gemcitabine or Acelarin
 (NUC-1031).

 -  All men or women of reproductive potential, unless using at least two contraceptive
 precautions, one of which must be from the list below, the other must be a condom* or
 abstaining from sexual intercourse, until six months after treatment has ended:

 -  Combined (oestrogen and progesterone containing) hormonal contraception
 associated with inhibition of ovulation: either oral, intravaginal or
 transdermal.

 -  Progesterone-only hormonal contraception associated with inhibition of ovulation:
 either oral, injectable or implantable.

 -  Intra-uterine device (IUD)

 -  Intra-uterine hormone-releasing system (IUS)

 -  Bilateral tubal occlusion

 -  Vasectomised partner *Male or female condom with or without spermicide is not an
 acceptable method of contraception alone.