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

• ClinicalTrials.gov Identifier: NCT03428958
• Recruitment Status: Recruiting
• First Posted: February 12, 2018
• Last Update Posted: January 25, 2023
• Sponsor: NuCana plc
• Information provided by (Responsible Party): NuCana plc

Tracking Information

• First Submitted Date: February 2, 2018
• First Posted Date: February 12, 2018
• Last Update Posted Date: January 25, 2023
• Actual Study Start Date: October 16, 2018
• Estimated Primary Completion Date: June 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 11, 2021)

• 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
• 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

Original Primary Outcome Measures (submitted: February 8, 2018)

• Number of patients reporting treatment-emergent adverse events [ Time Frame: 28 days ]
  Treatment-emergent adverse events will be assessed and graded by CTCAE 4.0
• Number of patients with treatment-emergent clinically significant changes in laboratory parameters, ECG changes, or changes in physical examinations [ Time Frame: 28 days ]
  Each will be assessed and graded by CTCAE 4.0

Current Secondary Outcome Measures (submitted: December 7, 2020)

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

Original Secondary Outcome Measures (submitted: February 8, 2018)

Tolerability of NUC-3373 in each combination cohort measured by dose intensity in Cycle 1 [ Time Frame: 28 days ]

Dose intensity will be measured by the actual dose received as compared to the projected dose to be administered in Cycle 1

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Safety, Pharmacokinetic and Efficacy Study of NUC-3373 in Combination With Standard Agents Used in Colorectal Cancer 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

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

Condition

• Colorectal Cancer
• Colorectal Neoplasms
• Colorectal Carcinoma
• Colorectal Tumors
• Neoplasms, Colorectal

Intervention

• Drug: NUC-3373 + leucovorin
  NUC-3373 + leucovorin
  Other Names:

  • folinic acid
  • levoleucovorin
  • Nucleotide analogue
• Drug: NUC-3373
  NUC-3373
  Other Name: Nucleotide analogue
• Drug: NUFOX
  NUC-3373 + oxaliplatin
  Other Names:

  • Eloxatin
  • Nucleotide analogue
• Drug: NUFOX + VEGF pathway inhibitor
  NUC-3373 + oxaliplatin + bevacizumab
  Other Names:

  • Eloxatin
  • Avastin
  • Nucleotide analogue
• Drug: NUFOX + EGFR inhibitor
  NUC-3373 + oxaliplatin + cetuximab/panitumumab
  Other Names:

  • Eloxatin
  • Erbitux
  • Nucleotide analogue
  • Vectibix
• Drug: NUFIRI
  NUC-3373 + irinotecan
  Other Names:

  • Campto
  • Camptosar
  • Nucleotide analogue
• Drug: NUFIRI + VEGF pathway inhibitor
  NUC-3373 + irinotecan + bevacizumab
  Other Names:

  • Campto
  • Camptosar
  • Avastin
  • Nucleotide analogue
• Drug: NUFIRI + EGFR inhibitor
  NUC-3373 + irinotecan + cetuximab/panitumumab
  Other Names:

  • Campto
  • Camptosar
  • Erbitux
  • Nucleotide analogue
  • Vectibix
• Drug: NUC-3373 + bevacizumab
  NUC-3373 + bevacizumab
  Other Names:

  • Nucleotide analogue
  • Avastin

Study Arms

• 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.
  Intervention: Drug: NUC-3373 + leucovorin
• 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.
  Intervention: Drug: NUC-3373
• 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.
  Intervention: Drug: NUC-3373 + leucovorin
• 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.
  Intervention: Drug: NUC-3373 + leucovorin
• 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.
  Intervention: Drug: NUFOX
• 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.
  Intervention: Drug: NUFIRI
• 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.
  Intervention: Drug: NUFOX
• 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.
  Intervention: Drug: NUFIRI
• 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.
  Intervention: Drug: NUFOX + VEGF pathway inhibitor
• 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.
  Intervention: Drug: NUFOX + VEGF pathway inhibitor
• 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.
  Intervention: Drug: NUFIRI + VEGF pathway inhibitor
• 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.
  Intervention: Drug: NUFIRI + VEGF pathway inhibitor
• 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.
  Intervention: Drug: NUC-3373 + bevacizumab
• 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.
  Intervention: Drug: NUFOX + EGFR inhibitor
• 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.
  Intervention: Drug: NUFIRI + EGFR inhibitor

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 11, 2021): 225
• Original Estimated Enrollment (submitted: February 8, 2018): 62
• Estimated Study Completion Date: June 2023
• Estimated Primary Completion Date: June 2023 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

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

• Listed Location Countries: France, United Kingdom, United States

Administrative Information

• NCT Number: NCT03428958
• Other Study ID Numbers: NuTide:302; 2017-002062-53 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: NuCana plc
• Original Responsible Party: Same as current
• Current Study Sponsor: NuCana plc
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Elisabeth Oelmann, MD PhD; NuCana plc

• PRS Account: NuCana plc
• Verification Date: January 2022