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A Safety, Pharmacokinetic and Efficacy Study of NUC-3373 in Combination With Standard Agents Used in Colorectal Cancer Treatment

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03428958
Recruitment Status : Recruiting
First Posted : February 12, 2018
Last Update Posted : January 25, 2023
Sponsor:
Information provided by (Responsible Party):
NuCana plc

Study Description
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Brief Summary:
This is a three-part study of NUC-3373 administered by intravenous (IV) infusion across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (leucovorin, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab). The primary objective is to identify a recommended dose and schedule for NUC-3373 when combined with these agents.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Colorectal Neoplasms Colorectal Carcinoma Colorectal Tumors Neoplasms, Colorectal Drug: NUC-3373 + leucovorin Drug: NUC-3373 Drug: NUFOX Drug: NUFOX + VEGF pathway inhibitor Drug: NUFOX + EGFR inhibitor Drug: NUFIRI Drug: NUFIRI + VEGF pathway inhibitor Drug: NUFIRI + EGFR inhibitor Drug: NUC-3373 + bevacizumab Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 225 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

This is a three-part study of NUC-3373 administered by IV across two administration schedules, either as monotherapy or as part of various combinations with agents commonly used to treat CRC (LV, oxaliplatin, irinotecan, bevacizumab, cetuximab and panitumumab).

Part 1 will determine if NUC-3373 should be administered with LV. Part 2 consists of a dose escalation phase, to assess the safety/tolerability of different doses of NUC-3373 in combination with either oxaliplatin (NUFOX) or irinotecan (NUFIRI), and an expansion phase, to assess weekly schedules of NUFOX and NUFIRI regimens selected in the escalation phase. Part 3 will assess the safety/efficacy of NUFOX and NUFIRI regimens administered in combination with bevacizumab, cetuximab or panitumumab.

Additional patients may be enrolled in all parts to replace patients who withdraw prior to completing the 28-day safety evaluation period to complete the min number patients per cohort. Enrolment may be expanded at the DSMCs discretion.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Open Label Study to Assess the Safety and Pharmacokinetics of NUC-3373, a Nucleotide Analogue, Given in Combination With Standard Agents Used in Colorectal Cancer Treatment
Actual Study Start Date : October 16, 2018
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : June 2023
Arms and Interventions
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Arm Intervention/treatment
Experimental: NUC-3373 + leucovorin (LV) fortnightly
Arm 1a: NUC-3373 administered IV followed by a 2-week washout period. The next dose of NUC-3373 administered in combination with LV at 400 mg/m2. All subsequent doses of NUC-3373 administered in combination with LV every 2 weeks in 28-day cycles.
 Drug: NUC-3373 + leucovorin
NUC-3373 + leucovorin
Other Names:
  • folinic acid
  • levoleucovorin
  • Nucleotide analogue
Experimental: NUC-3373 fortnightly
Arm 1b: LV 400 mg/m2 administered IV over 2 hours prior to NUC-3373 infusion followed by a 2-week washout period. Then, NUC-3373 administered IV every 2 weeks without LV in 28-day cycles.
 Drug: NUC-3373
NUC-3373
Other Name: Nucleotide analogue
Experimental: NUC-3373 + leucovorin (LV) weekly
Arm 1c: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 administered IV weekly on Days 1, 8, 15 and 22 of 28-day cycles.
 Drug: NUC-3373 + leucovorin
NUC-3373 + leucovorin
Other Names:
  • folinic acid
  • levoleucovorin
  • Nucleotide analogue
Experimental: NUC-3373 + leucovorin (LV); combination chemotherapy ineligible
Arm 1d: LV 400 mg/m2 administered IV over 2 hours followed by NUC-3373 administered IV on Days 1, 8, 15 and 22 of 28-day cycles.
 Drug: NUC-3373 + leucovorin
NUC-3373 + leucovorin
Other Names:
  • folinic acid
  • levoleucovorin
  • Nucleotide analogue
Experimental: NUC-3373 + oxaliplatin weekly
Arm 2a: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with oxaliplatin (85 mg/m2) administered on Days 1 and 15.
 Drug: NUFOX
NUC-3373 + oxaliplatin
Other Names:
  • Eloxatin
  • Nucleotide analogue
Experimental: NUC-3373 + irinotecan weekly
Arm 2b: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.
 Drug: NUFIRI
NUC-3373 + irinotecan
Other Names:
  • Campto
  • Camptosar
  • Nucleotide analogue
Experimental: NUC-3373 + oxaliplatin (NUFOX) expansion
Arm 2c: At the completion of Arm 2a, the recommended dose of NUC-3373 (+LV 400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with oxaliplatin (85 mg/m2) administered on Days 1 and 15.
 Drug: NUFOX
NUC-3373 + oxaliplatin
Other Names:
  • Eloxatin
  • Nucleotide analogue
Experimental: NUC-3373 + irinotecan (NUFIRI) expansion
Arm 2d: At the completion of Arm 2b, the recommended dose of NUC-3373 (+LV 400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with irinotecan (180 mg/m2) on Days 1 and 15.
 Drug: NUFIRI
NUC-3373 + irinotecan
Other Names:
  • Campto
  • Camptosar
  • Nucleotide analogue
Experimental: NUFOX + bevacizumab weekly
Arm 3a: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2c will be combined with bevacizumab. NUC-3373+LV will be administered weekly, oxaliplatin will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.
 Drug: NUFOX + VEGF pathway inhibitor
NUC-3373 + oxaliplatin + bevacizumab
Other Names:
  • Eloxatin
  • Avastin
  • Nucleotide analogue
Experimental: NUFOX + bevacizumab fortnightly
Arm 3b: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2c will be combined with bevacizumab. NUC-3373+LV+oxaliplatin will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.
 Drug: NUFOX + VEGF pathway inhibitor
NUC-3373 + oxaliplatin + bevacizumab
Other Names:
  • Eloxatin
  • Avastin
  • Nucleotide analogue
Experimental: NUFIRI + bevacizumab weekly
Arm 3c: NUC-3373, LV and irinotecan at dose levels used in Arm 2d will be combined with bevacizumab. NUC-3373+LV will be administered weekly, irinotecan will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.
 Drug: NUFIRI + VEGF pathway inhibitor
NUC-3373 + irinotecan + bevacizumab
Other Names:
  • Campto
  • Camptosar
  • Avastin
  • Nucleotide analogue
Experimental: NUFIRI + bevacizumab fortnightly
Arm 3d: NUC-3373, LV and irinotecan at dose levels used in Arm 2d will be combined with bevacizumab. NUC-3373+LV+irinotecan will be administered fortnightly and bevacizumab will be administered in accordance with standard local practice.
 Drug: NUFIRI + VEGF pathway inhibitor
NUC-3373 + irinotecan + bevacizumab
Other Names:
  • Campto
  • Camptosar
  • Avastin
  • Nucleotide analogue
Experimental: NUC-3373 + LV + bevacizumab; maintenance patients
Arm 3e: NUC-3373+LV (400 mg/m2) administered weekly on Days 1, 8, 15 and 22 of 28-day cycles in combination with bevacizumab and bevacizumab will be administered in accordance with standard local practice.
 Drug: NUC-3373 + bevacizumab
NUC-3373 + bevacizumab
Other Names:
  • Nucleotide analogue
  • Avastin
Experimental: NUFOX + cetuximab
Arm 3f: NUC-3373, LV and oxaliplatin at dose levels used in Arm 2c may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or fortnightly, oxaliplatin will be administered fortnightly and cetuximab will be administered in accordance with standard local practice.
 Drug: NUFOX + EGFR inhibitor
NUC-3373 + oxaliplatin + cetuximab/panitumumab
Other Names:
  • Eloxatin
  • Erbitux
  • Nucleotide analogue
  • Vectibix
Experimental: NUFIRI + cetuximab
Arm 3g: NUC-3373, LV and irinotecan at dose levels used in Arm 2d may be administered in subsequent cetuximab cohorts. NUC-3373+LV may be administered weekly or fortnightly, irinotecan will be administered fortnightly and cetuximab will be administered in accordance with standard local practice.
 Drug: NUFIRI + EGFR inhibitor
NUC-3373 + irinotecan + cetuximab/panitumumab
Other Names:
  • Campto
  • Camptosar
  • Erbitux
  • Nucleotide analogue
  • Vectibix


Outcome Measures
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Primary Outcome Measures :
  1. Number of patients reporting treatment-emergent adverse events (TEAEs) [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]
    Treatment-emergent adverse events will be assessed and graded by CTCAE v5.0

  2. Number of patients with treatment-emergent clinically significant changes in laboratory parameters, ECG changes, or changes in physical examinations [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]
    Each will be assessed and graded by CTCAE v5.0


Secondary Outcome Measures :
  1. Tolerability of NUC-3373 in each combination cohort measured by dose intensity in Cycle 1 [ Time Frame: Assessed from baseline to 30 days after last dose of study drug ]
    Dose intensity will be measured by the actual dose received as compared to the projected dose to be administered in Cycle 1


Eligibility Criteria
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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:

All patients

  1. Provision of written informed consent
  2. Have histological confirmation of CRC with evidence of locally advanced/unresectable or metastatic disease
  3. Age ≥18 years
  4. Life expectancy of ≥12 weeks
  5. ECOG Performance status 0 or 1
  6. Measurable disease as defined by RECIST v1.1
  7. Known RAS and BRAF status
  8. Adequate bone marrow function as defined by: ANC ≥1.5×10^9/L, platelet count ≥100×10^9/L (with no evidence of bleeding), and haemoglobin ≥9 g/dL
  9. Adequate liver function as defined by serum total bilirubin ≤1.5×ULN, AST and ALT ≤2.5×ULN (or ≤5×ULN if liver metastases present)
  10. Adequate renal function assessed as serum creatinine <1.5×ULN or glomerular filtration rate ≥50 mL/min. This criterion does not apply to Arm 1d.
  11. Serum albumin ≥3 g/dL
  12. For the cohort in which the patient will participate, there are no contra-indications to receiving the approved partner combination drugs
  13. Ability to comply with protocol requirements
  14. Female patients of child-bearing potential must have a negative pregnancy test within 7 days prior to the first study drug administration. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy. Male patients and female 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.
  15. Patients must have been advised to take measures to avoid or minimise exposure to UV light for the duration of study participation and for a period of 4 weeks following the last dose of study medication
  16. Male patients receiving oxaliplatin must have been offered advice on and/or sought counselling for conservation of sperm prior to the first dose of study medication

>3rd-line patients

  1. Received at least two prior lines of therapy for locally advanced or metastatic CRC, including one fluoropyrimidine plus oxaliplatin and one fluoropyrimidine plus irinotecan containing regimen. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included.
  2. Patients due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
  3. Patients due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based therapy

2nd-/3rd-line patients

  1. Received at least one but no more than two prior lines of fluoropyrimide-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included.
  2. Patients in Part 2 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
  3. Patients in Part 2 due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen

Combination chemotherapy ineligible patients

  1. May have received one prior fluoropyrimidine-containing regimen for locally advanced or metastatic CRC
  2. Ineligible to receive combination therapy for locally advanced or metastatic CRC
  3. Creatinine clearance >30mL/min

Rapid progressors

  1. Received no more than two prior lines of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received FOLFOXIRI-based regimens in 1st-/2nd-line settings may be included.
  2. Have had tumour progression ≤3 months of starting the last fluoropyrimide-containing regimen
  3. Patients in Part 2 or 3 due to receive NUFOX should be suitable for re-challenge with an oxaliplatin-based regimen
  4. Patients in Part 2 or 3 due to receive NUFIRI should be suitable for re-challenge with an irinotecan-based regimen

2nd-line patients

1. Received one prior line of fluoropyrimidine-containing therapy in combination with oxaliplatin and/or irinotecan for locally advanced or metastatic CRC. Previous treatment with SoC regimens in combination with molecular targeted therapies is permitted and patients who received triplet chemotherapy based regimens is allowed.

Maintenance patients

  1. Received at least 12 weeks of 1st-line SoC therapy for locally advanced or metastatic CRC and achieved at least stable disease
  2. Eligible for maintenance therapy

Exclusion Criteria:

All patients

  1. Prior history of hypersensitivity or current contra-indications to 5-FU or capecitabine
  2. Prior history of hypersensitivity or current contra-indications to any of the combination agents required for the study arm to which the patient is assigned
  3. History of allergic reactions attributed to the components of the NUC-3373 drug product formulation
  4. Symptomatic CNS or leptomeningeal metastases
  5. Symptomatic ascites, ascites currently requiring drainage procedures or ascites requiring drainage over the prior 3 months
  6. Chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), immunotherapy or exposure to another investigational agent within 28 days (or five times half-life for a biological agent or three times the half-life for an immunotherapy agent) of first receipt of study drug
  7. Residual toxicities from prior chemotherapy or radiotherapy, which have not regressed to Grade ≤1 severity (CTCAE v5.0) except for alopecia. In cohorts not containing oxaliplatin, residual Grade 2 neuropathy is allowed.
  8. History of another malignancy diagnosed within the past 5 years, with the exception of adequately treated non-melanoma skin cancer curatively treated carcinoma in situ of the cervix, surgically excised or potentially curatively treated ductal carcinoma in situ of the breast, or low grade prostate cancer or patients after prostatectomy not requiring treatment. Patients with previous invasive cancers are eligible if treatment was completed more than 3 years prior to initiating the current study treatment and there is no evidence of recurrence.
  9. Presence of active bacterial or viral infection (including SARS-CoV-2, Herpes Zoster or chicken pox), known HIV positive or known active hepatitis B or C
  10. Presence of any uncontrolled concurrent serious illness, medical condition 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 the results
  11. Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location) that, in the judgment of the Investigator, may affect the patient's ability to sign the informed consent and undergo study procedures
  12. Currently pregnant, lactating or breastfeeding
  13. QTc interval >450 milliseconds for males and >470 milliseconds for females
  14. Required concomitant use of drugs known to prolong QT/QTc interval
  15. Irinotecan cohorts: use of strong CYP3A4 inducers within 2 weeks of first dose of study drug or use of strong CYP3A4 or UGT1A1 inhibitors within 1 week of first dose of study drug
  16. Has received a live vaccination within four weeks of first planned dose of study medication
  17. Known DPD or TYMP mutations associated with toxicity to fluoropyrimidines
  18. Use of warfarin and other types of long acting anti-coagulants is prohibited within 4 weeks of the first dose of study treatment

Patients receiving bevacizumab

  1. Patients with a history of haemoptysis (≥1/2 tsp of red blood)
  2. Wound healing complications or surgery within 28 days of starting bevacizumab
  3. Severe chronic wounds, ulcers or bone fracture
  4. Arterial thromboembolic events or haemorrhage within 6 months prior to study entry (except for tumour bleeding surgically treated by tumour resection)
  5. Bleeding diatheses or coagulopathy
  6. Receiving full-dose anti-coagulation treatment
  7. Uncontrolled hypertension
  8. Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia
  9. Severe proteinuria
  10. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea
  11. Any contraindications present in the bevacizumab Prescribing Information

Patients receiving cetuximab or panitumumab

  1. Clinically significant coronary heart disease or myocardial infarction within the last 12 months or high risk of uncontrolled arrhythmia
  2. Acute or subacute ileus, chronic inflammatory bowel disease or chronic diarrhoea
  3. Hypomagnesaemia or hypokalaemia not controlled by oral therapy
  4. Any contraindications present in the cetuximab or panitumumab Prescribing Information
Contacts and Locations
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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): NCT03428958


Contacts
Layout table for location contacts
Contact: NuTide:302 Information +44 (0)131 357 1111 NuTide302@nucana.com
Contact: Elisabeth Oelmann, MD PhD +44 (0)131 357 1118 elisabethoelmann@nucana.com

Locations
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United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
United States, Washington
Seattle Cancer Center Recruiting
Seattle, Washington, United States, 98109-1023
Compass Oncology Recruiting
Vancouver, Washington, United States, 98684
France
Hopital Franco-Britannique Recruiting
Levallois-Perret, France, 92300
United Kingdom
The Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0YN
University College London Hospitals NHS Foundation Trust Recruiting
London, United Kingdom, W1T 7HA
University of Oxford Recruiting
Oxford, United Kingdom, OX3 7LE
Sponsors and Collaborators
NuCana plc
Investigators
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Study Director: Elisabeth Oelmann, MD PhD NuCana plc
More Information
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Responsible Party: NuCana plc
ClinicalTrials.gov Identifier: NCT03428958    
Other Study ID Numbers: NuTide:302
2017-002062-53 ( EudraCT Number )
First Posted: February 12, 2018    Key Record Dates
Last Update Posted: January 25, 2023
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by NuCana plc:
Relapsed metastatic adenocarcinoma of colon/rectum
Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Bevacizumab
Cetuximab
Panitumumab
 Oxaliplatin
Irinotecan
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antidotes
Protective Agents
Vitamin B Complex
Vitamins
Micronutrients