NUC-1031 in Patients With Advanced Solid Tumours (ProGem1)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by Imperial College London
Sponsor:
Collaborator:
NuCana Biomed Ltd
Information provided by (Responsible Party):
Imperial College London
ClinicalTrials.gov Identifier:
NCT01621854
First received: June 14, 2012
Last updated: March 27, 2013
Last verified: March 2013
  Purpose

This is a two-part Phase I, open label, dose-escalation, study of NUC-1031 as a single agent in patients with advanced solid tumours who have failed to respond to or who have relapsed after treatment with standard therapy. NUC-1031 is a ProTide of gemcitabine, a drug that has been used widely and effectively against cancers for many years. Both NUC-1031 and gemcitabine work by preventing cancer cells from dividing by attacking their DNA (deoxyribonucleic acid). Non clinical studies have shown that NUC-1031 is more effective than gemcitabine because it is able to reach cancer cells by passive diffusion, is less easily degraded by the cancer cell, and delivers the monophosphate form of the active agent. The first part of the study is to determine recommended phase 2 dose by dose escalation and the second part is to explore preliminary anti-tumour activity.


Condition Intervention Phase
Cancer
Drug: NUC-1031
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two-part, Phase I Open Label Dose-escalation Study to Assess the Safety, Pharmacokinetics and Clinical Activity of NUC-1031, a Nucleoside Analogue, in Patients With Advanced Solid Tumours.

Resource links provided by NLM:


Further study details as provided by Imperial College London:

Primary Outcome Measures:
  • To determine the RP2D of NUC-1031 administered as either an I.V. weekly or twice-weekly schedule in patients with advanced solid tumours. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Adverse events (AE) and changes from baseline in vital signs, clinical laboratory parameters, and electrocardiography (ECG) assessments will be assessed

  • To further evaluate the safety profile of NUC-1031 in an expanded cohort at RP2D in patients with advanced pancreatic, ovarian, NSCL, breast or bladder cancer. [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Adverse events (AE) and changes from baseline in vital signs, clinical laboratory parameters, and electrocardiography (ECG) assessments


Secondary Outcome Measures:
  • To determine the pharmacokinetics of NUC-1031 and its metabolites. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    PK endpoints will include assessments such as systemic Clearance (CL), Apparent Volume of Distribution (Vd), Area Under the Curve (AUC), Maximum plasma (peak) drug concentration after single dose administration (Cmax), and t1/2.

  • To explore the preliminary anti-tumour activity of NUC-1031 [given at the RP2D and preferred schedule selected from Part I] in patients with advanced pancreatic, ovarian, NSCL, breast or bladder cancer. [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    Assessment of anti-tumour activity as defined by RECIST version 1.1

    Urinary excretion of NUC-1031 and metabolites.



Estimated Enrollment: 59
Study Start Date: October 2012
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NUC-1031
Cohort 1, Schedule A, NUC-1031 I.V. 1000mg/m2, Days 1, 8, & 15 every 28 days Cohort 1, Schedule B, NUC-1031 I.V. 500mg/m2, Days 1 & 5, 8 & 12, 15 &19 every 28 days Cohort 2, Schedule A, NUC-1031 I.V. 2000mg/m2, Days 1, 8, & 15 every 28 days Cohort 2, Schedule B, NUC-1031 I.V. 1000mg/m2, Days 1 & 5, 8 & 12, 15 &19 every 28 days
Drug: NUC-1031
Cohort 1, Schedule A, NUC-1031 I.V. 1000mg/m2, Days 1, 8, & 15 every 28 days Cohort 1, Schedule B, NUC-1031 I.V. 500mg/m2, Days 1 & 5, 8 & 12, 15 &19 every 28 days Cohort 2, Schedule A, NUC-1031 I.V. 2000mg/m2, Days 1, 8, & 15 every 28 days Cohort 2, Schedule B, NUC-1031 I.V. 1000mg/m2, Days 1 & 5, 8 & 12, 15 &19 every 28 days

Detailed Description:

This is a two-part, Phase I, open label study of NUC-1031 as a single agent, administered IV weekly on days 1, 8, & 15 (Schedule A) or twice weekly on days 1 & 5, 8 & 12, 15 &19 (Schedule B) of a 28 day- cycle regimen. An initial dose-escalation phase (Part I) will be followed by an expansion cohort phase (Part II) using the preferred regimen from Part 1. In Part I, sequential patients will be assigned to increasing doses of NUC-1031 in a standard '3 + 3' design to determine the recommended Phase II dose (RP2D). There will be a mandatory review of all available data (in particular the safety profile and preliminary PK data through to at least the last scheduled day of Cycle 1) following enrolment of the second cohort of both schedule A and B to select the preferred administration schedule to take forward for ongoing evaluation. Subsequently, safety review will be conducted prior to enrolment of new subjects after every 2 planned dose levels and prior to definition of RP2D.

In Part II (dose expansion) additional patients will be enrolled to receive NUC-1031 at the RP2D and dosing frequency determined from Part I of the study. To be eligible to enter Part II, patients must have a diagnosis of cancer of the pancreas, ovary, lung (NSCL), breast, or bladder. During Part II, further information will be obtained regarding safety, PK, PD and preliminary anti-tumour efficacy of NUC-1031 at RP2D.

In both parts of the study, patients may continue to receive NUC-1031 for up to 6 cycles or until disease progression, the occurrence of unmanageable drug related toxicity despite dose modification or if the study participant declines further treatment.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of signed written informed consent.
  2. Diagnosis:

    1. Part I: Histologically or cytologically confirmed diagnosis of cancer which is not amenable to standard therapy, is refractory to standard therapy or for which no standard therapy exists.
    2. Part II: Histologically or cytologically confirmed diagnosis of advanced or metastatic cancer of the pancreas, ovary, lung (NSCL), breast, bladder or NHL not amenable to standard therapy, refractory to standard therapy or for which no standard therapy exists who have been previously treated with gemcitabine.
  3. Age ≥ 18 years.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 5. Life expectancy of ≥ 12 weeks.

6. Disease measurability:

  1. Part I (Dose-escalation):

    Patients must have a measurable (as per RECIST criteria version 1.1) and/or evaluable disease (e.g., cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions which do not fulfill RECIST criteria version 1.1 for measurable disease).

  2. Part II (expansion cohort):

    Patients must have at least one measurable disease lesion as per the RECIST criteria version 1.1.

    7. Formalin Fixed Paraffin-Embedded (FFPE) archival tumour tissue available (for Part II only). Fresh biopsies will be required if no FFPE tumour tissues available (for Part II only).

    8. Adequate bone marrow function as defined by: WBC of ≥ 3 x109/L, ANC of ≥ 1.5 x 109/L, platelet count of ≥ 100.0 x 109/L, and hemoglobin of ≥ 10 g/dL.

    9. Adequate liver function, as determined by: Serum total bilirubin ≤1.5 x ULN (≤2.5 x ULN if liver metastases), AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases).

    10. Adequate renal function assessed by at least one of the following: 1) Serum creatinine ≤ 1.5 x ULN; or 2) creatinine clearance estimate of ≥ 60 mL/min in male and ≥ 50 mL/min in female (as calculated according to Cockcroft-Gault formula).

    11. Ability to comply with protocol requirements. 12. Female patients must be postmenopausal (12 months of amenorrhea), surgically sterile or they must agree to use a physical method of contraception. Oral or injectable contraceptive agents cannot be the sole method of contraception. Male patients must be surgically sterile or agree to use a barrier method of contraception.

    13. Female patients of child-bearing potential must have a negative serum pregnancy test within the seven days prior to the first study drug administration.

    Exclusion Criteria:

    1. History of allergic reactions attributed to previous gemcitabine treatment.
    2. Symptomatic CNS or leptomeningeal metastases
    3. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), or immunotherapy within 28 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C). Hormone therapy within 14 days of first receipt of study drug.
    4. Prior toxicities from chemotherapy or radiotherapy which have not regressed to Grade ≤ 1 severity (NCI-CTCAE version 4.0) apart from neuropathy and alopecia.
    5. Another active cancer (excluding basal cell carcinoma or cervical intraepithelial neoplasia (CIN/cervical in situ or melanoma in situ; Part II only).
    6. Patients with uncontrolled concomitant illness, active infection requiring i.v. antibiotics, or uncontrolled infections, or a fever >38.5°C on the day of scheduled dosing.
    7. Patients will serious illnesses, medical conditions, or other medical history, including laboratory results, which, in the investigator's opinion, would be likely to interfere with a patient's participation in the study, or with the interpretation of the results.
    8. Known HIV or known active Hepatitis B or C.
    9. Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the investigator, may affect the patient's ability to sign the informed consent and undergo study procedures.

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  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01621854

Contacts
Contact: Sarah Blagden 0208 383 8370 s.blagden@imperial.ac.uk

Locations
United Kingdom
NIHR/Wellcome Trust Imperial CRF Recruiting
London, Hammersmith, United Kingdom, W12 0HS
Principal Investigator: Sarah Blagden, PhD FRCP         
Sponsors and Collaborators
Imperial College London
NuCana Biomed Ltd
Investigators
Principal Investigator: Dr Blagden, PhD FRCP Imperial College London
  More Information

No publications provided

Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT01621854     History of Changes
Other Study ID Numbers: CRO1964
Study First Received: June 14, 2012
Last Updated: March 27, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Imperial College London:
cancer
nucleoside analogue
advanced solid tumours

ClinicalTrials.gov processed this record on September 29, 2014