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A Safety Study of NUC-7738 in Patients With Advanced Solid Tumours or Lymphoma

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ClinicalTrials.gov Identifier: NCT03829254
Recruitment Status : Recruiting
First Posted : February 4, 2019
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
NuCana plc

Brief Summary:

This is a two-part, Phase I, dose-escalation study of NUC-7738 administered by intravenous infusion across two administration schedules.

Part 1 is a dose-escalation study in patients with advanced solid tumours to assess the safety and tolerability of NUC-7738, in addition to establishing the recommended phase II dose (RP2D) and dose administration schedule of NUC-7738 for further exploration in Part 2 of the study.

Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of up to 20 additional patients with advanced solid tumours and an additional 12 patients with lymphoma.


Condition or disease Intervention/treatment Phase
Advanced Cancer Lymphoma Solid Tumor Drug: NUC-7738 Phase 1

Detailed Description:

Part 1:

The study will commence with weekly administration, the starting dose for the first cohort will be 14 mg/m2. Dose escalation will begin with a modified 1+1 accelerated titration cohort design. A single patient will be treated in each sequential dosing cohort, with dose escalation allowed if ≤1 moderate safety observation (MSO) is reported during the 14-day dose-limiting toxicity (DLT) observation period. A MSO is defined as an adverse event (AE) meeting Common Terminology Criteria for Adverse Events (CTCAE) of Grade 2 criteria or higher, is clinically significant, probably or definitely related to NUC-7738, and unrelated to underlying disease or fatigue. If two or more MSOs are documented in the first patient in the cohort, a second patient will be enrolled. If ≤1 MSOs are reported in the second patient, dose escalation will continue using the 1+1 design. If two or more MSOs are noted in the second patient, or upon evidence of a DLT in any patient, the study will revert to the classical 3+3 design. Upon expansion to the 3+3 design in any dosing cohort, all subsequent dosing cohorts will be conducted using the 3+3 design. Following treatment of the first patient in an expanded 3+3 cohort, the second and third patient will be treated no earlier than 7 days following Cycle 1 Day 1 for the prior patient (i.e., there will be a gap of 7 days between treatment of the first patient and treatment of the second and third patient in an expanded cohort).

Upon expansion to the classical 3+3 design in the weekly cohort, if deemed appropriate by the Trial Management Group (based on a review of safety data, clinical activity, and available pharmacokinetic [PK] and pharmacodynamic [PD] data), the fortnightly schedule of administration will be triggered. The fortnightly schedule of administration will be explored only in the 3+3 cohort design and will be closed to enrolment of patients until the RP2D has been determined in the weekly dose administration cohort.

It is anticipated that approximately 17 patients will be required to complete the weekly dose escalation stage of Part 1, with a further 12 patients required to explore the fortnightly schedule.

Part 2:

This part of the study will further characterise the safety of NUC-7738 and assess preliminary efficacy signals at the RP2D and dose administration schedule (determined in Part 1) in an expansion cohort.

In the absence of unacceptable toxicity, patients from Part 1 and 2 can remain on study and continue to receive NUC-7738 until disease progression.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 61 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Two-part, Phase I, Open-label, Dose-escalation and Expansion Study to Assess the Safety, Pharmacokinetics and Clinical Activity of NUC-7738, a Nucleotide Analogue, in Patients With Advanced Solid Tumours or Lymphoma.
Actual Study Start Date : June 17, 2019
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: NUC-7738
NUC-7738 administered by intravenous infusion on a weekly or fortnightly schedule. In the weekly dosing schedule, NUC-7738 is administered on Days 1 and 8 of a 14-day cycle. In the fortnightly dosing schedule, NUC-7738 is administered on Day 1 of a 14-day cycle.
Drug: NUC-7738
NUC-7738
Other Name: Nucleotide Analogue




Primary Outcome Measures :
  1. Number of patients with dose-limiting toxicities [ Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered ]
    Safety and tolerability of NUC-7738

  2. Number of patients with treatment-emergent adverse events (CTCAE v5.0) [ Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered ]
    Safety and tolerability of NUC-7738

  3. Number of patients with clinically significant laboratory changes (CTCAE v5.0) [ Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered ]
    Safety and tolerability of NUC-7738

  4. Number of patients with changes in physical exam, vital signs, and serial electrocardiograms. [ Time Frame: From the date of consent until 30 days after the last dose of NUC-7738 administered ]
    Safety and tolerability of NUC-7738

  5. RP2D for NUC-7738 administered via weekly and fortnightly dosing schedules [ Time Frame: Until completion of Part 1 (an average of 1 year) ]
    Part 1 only


Secondary Outcome Measures :
  1. Plasma and /or peripheral blood mononuclear cell levels of NUC-7738 and its metabolites [ Time Frame: Samples collected on Days 1, 2, and 3 of Cycle 1 and Days 1 and 2 of Cycle 2 (each cycle is 14 days) ]
    Pharmacokinetics

  2. Percentage change from baseline in tumour size [ Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months) ]

    Efficacy (per RECIST v 1.1 or Cheson et al, 2007):

    The percentage change in the sum of longest diameters of target lesions from baseline to Week 8.

    The best percentage change in the sum of longest diameters of target lesions from baseline to best on-treatment measurement


  3. Objective response rate [ Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months) ]
    Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the number of patients achieving a confirmed response (complete response [CR] or partial response [PR])

  4. Duration of response [ Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months) ]
    Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for CR or PR until the first date that recurrence or progressive disease (PD) is objectively documented (responders only)

  5. Disease control rate [ Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months) ]
    Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the proportion of patients achieving confirmed response (CR and PR) or stable disease (SD) as the best overall response

  6. Duration of stable disease [ Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months) ]
    Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from the time measurement criteria are first met for SD until the first date that recurrence or PD is objectively documented

  7. Progression free survival [ Time Frame: Assessed every 8 weeks following Day 1 up to and including Cycle 12 (each cycle is 14 days), moving to every 12 weeks until the end of study (up to 22 months) ]
    Efficacy (per RECIST v 1.1 or Cheson et al, 2007): defined as the time from first dose of study treatment until the date of objective disease progression or death



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of signed written informed consent
  2. Histologically confirmed diagnosis of an advanced solid tumour (Part 1 and 2) or lymphoma (Part 2 only), which is not amenable to standard chemotherapy, is refractory to standard chemotherapy, or for which no standard chemotherapy exists
  3. Age ≥18 years (no upper age limit)
  4. Eastern Cooperative Oncology Group performance status of 0 or 1
  5. Life expectancy of ≥12 weeks
  6. Part 1 and Part 2: enrolment of patients with advanced solid tumours. Patients must have measurable disease as per RECIST v1.1 criteria and/or evaluable disease (evaluable: cytologically or radiologically detectable disease such as ascites, peritoneal deposits, or lesions, which do not fulfil RECIST v1.1 criteria for measurable disease) for solid tumours.
  7. Part 2: enrolment of patients with lymphoma. Patients must have bi-dimensionally measurable disease as per Cheson et al, 2007 criteria for lymphoma.
  8. Adequate bone marrow, liver, and renal function
  9. Ability to comply with protocol requirements
  10. Patients of child-bearing potential must agree to practice true abstinence or to use two highly effective forms of contraception, one of which must be a barrier method of contraception, from the time of screening until 30 days after the last dose of study medication.
  11. Willing to undergo biopsy of suitably accessible lesions. Patients who do not have easily accessible tumour for biopsy should not be put at undue risk for sample collection and these patients remain eligible for the study.

Exclusion Criteria:

  1. History of allergic reaction fo any of the components of NUC-7738
  2. Central nervous system or leptomeningeal metastases
  3. Chemotherapy, radiotherapy (other than a short cycle of palliative radiotherapy for bone pain), immunotherapy, or exposure to another investigational agent within 28 days (or five times the half-life for a biologic agent) of first administration of the IMP:

    a For nitrosoureas and mitomycin C within 6 weeks of first administration of NUC-7738 b For hormone therapy within 14 days of first administration of NUC-7738 c Corticosteroid treatment is allowed during the screening period but should be weaned to a dose of 10 mg prednisolone (or steroids equivalent) by Cycle 1 Day 1.

  4. Prior toxicities from anti-cancer agents or radiotherapy, which have not regressed to Grade ≤1 severity (NCI-CTCAE v5.0), excluding neuropathy and alopecia
  5. Presence of any uncontrolled concomitant illness, serious illness, medical conditions, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with their participation in the study, or with the interpretation of results, including the following:

    a Congestive heart failure (New York Heart Association Class III or Class IV) b Myocardial infarction within 6 months of the first dose of study medication c Unstable or poorly controlled angina pectoris d Complete left bundle branch, bifasicular block or other clinically significant abnormal electrocardiogram finding e A history of or current risk factor for Torsades de Point (e.g., heart failure, hypokalaemia, or a family history of long QT syndrome) f A history of, or current diagnosis of, interstitial pneumonitis or pulmonary fibrosis

  6. Known human immunodeficiency virus positive or known active hepatitis B or C. Presence of an active bacterial or viral infection including Herpes zoster or chicken pox
  7. 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
  8. Currently pregnant, lactating or breastfeeding
  9. QTc interval >450 milliseconds for males and >470 milliseconds for females
  10. Concomitant use of drugs known to prolong QT/QTc interval
  11. Have received a live vaccination within four weeks of first planned dose of study medication.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03829254


Contacts
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Contact: Anthea Gates +44(0)7741572444 Anthea.Gates@precisionformedicine.com

Locations
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United Kingdom
University of Edinburgh Recruiting
Edinburgh, United Kingdom, EH4 2XR
Contact: Stefan Symeonides, MD         
Freeman Hospital Recruiting
Newcastle, United Kingdom, NE7 7DN
Contact: Ruth Plummer, MD         
University of Oxford Recruiting
Oxford, United Kingdom, OX3 7DQ
Contact: Sarah Blagden, MD         
Sponsors and Collaborators
NuCana plc
Investigators
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Study Director: Christopher B Wood, MD PhD NuCana plc

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Responsible Party: NuCana plc
ClinicalTrials.gov Identifier: NCT03829254     History of Changes
Other Study ID Numbers: NuTide:701
2018-003417-17 ( EudraCT Number )
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NuCana plc:
Solid tumors
Lymphoma
Cordycepin
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases