Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer

a single-centre, open-label, dose-escalation, phase 1 trial

Angela Alistar, Bonny B. Morris, Rodwige Desnoyer, Heidi D. Klepin, Keyanoosh Hosseinzadeh, Clancy Clark, Amy Cameron, John Leyendecker, Ralph D'Agostino, Umit Topaloglu, Lakmal W. Boteju, Asela R. Boteju, Rob Shorr, Zuzana Zachar, Paul M. Bingham, Tamjeed Ahmed, Sandrine Crane, Riddhishkumar Shah, John J. Migliano, Timothy S. Pardee & 5 others Lance Miller, Gregory Hawkins, Guangxu Jin, Wei Zhang, Boris Pasche

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

Original languageEnglish (US)
Pages (from-to)770-778
Number of pages9
JournalThe Lancet Oncology
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2017

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Pancreatic Neoplasms
Safety
Maximum Tolerated Dose
oxaliplatin
irinotecan
Lymphopenia
CPI 613
Anemia
Hypokalemia
Leucovorin
Neutropenia
Fluorouracil
Hyperglycemia
Thrombocytopenia
Neoplasms
Adenocarcinoma
Hypoalbuminemia

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Alistar, Angela ; Morris, Bonny B. ; Desnoyer, Rodwige ; Klepin, Heidi D. ; Hosseinzadeh, Keyanoosh ; Clark, Clancy ; Cameron, Amy ; Leyendecker, John ; D'Agostino, Ralph ; Topaloglu, Umit ; Boteju, Lakmal W. ; Boteju, Asela R. ; Shorr, Rob ; Zachar, Zuzana ; Bingham, Paul M. ; Ahmed, Tamjeed ; Crane, Sandrine ; Shah, Riddhishkumar ; Migliano, John J. ; Pardee, Timothy S. ; Miller, Lance ; Hawkins, Gregory ; Jin, Guangxu ; Zhang, Wei ; Pasche, Boris. / Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer : a single-centre, open-label, dose-escalation, phase 1 trial. In: The Lancet Oncology. 2017 ; Vol. 18, No. 6. pp. 770-778.
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title = "Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial",
abstract = "Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10{\%}, and more than 50{\%} of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55{\%}] patients), hypokalaemia (six [33{\%}]), peripheral sensory neuropathy (five [28{\%}]), diarrhoea (five [28{\%}]), and abdominal pain (four [22{\%}]). The most common grade 3–4 haematological adverse events were neutropenia (five [28{\%}] of 18 patients), lymphopenia (five [28{\%}]), anaemia (four [22{\%}], and thrombocytopenia in three [17{\%}]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94{\%}) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61{\%}) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.",
author = "Angela Alistar and Morris, {Bonny B.} and Rodwige Desnoyer and Klepin, {Heidi D.} and Keyanoosh Hosseinzadeh and Clancy Clark and Amy Cameron and John Leyendecker and Ralph D'Agostino and Umit Topaloglu and Boteju, {Lakmal W.} and Boteju, {Asela R.} and Rob Shorr and Zuzana Zachar and Bingham, {Paul M.} and Tamjeed Ahmed and Sandrine Crane and Riddhishkumar Shah and Migliano, {John J.} and Pardee, {Timothy S.} and Lance Miller and Gregory Hawkins and Guangxu Jin and Wei Zhang and Boris Pasche",
year = "2017",
month = "6",
day = "1",
doi = "10.1016/S1470-2045(17)30314-5",
language = "English (US)",
volume = "18",
pages = "770--778",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "6",

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Alistar, A, Morris, BB, Desnoyer, R, Klepin, HD, Hosseinzadeh, K, Clark, C, Cameron, A, Leyendecker, J, D'Agostino, R, Topaloglu, U, Boteju, LW, Boteju, AR, Shorr, R, Zachar, Z, Bingham, PM, Ahmed, T, Crane, S, Shah, R, Migliano, JJ, Pardee, TS, Miller, L, Hawkins, G, Jin, G, Zhang, W & Pasche, B 2017, 'Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial', The Lancet Oncology, vol. 18, no. 6, pp. 770-778. https://doi.org/10.1016/S1470-2045(17)30314-5

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer : a single-centre, open-label, dose-escalation, phase 1 trial. / Alistar, Angela; Morris, Bonny B.; Desnoyer, Rodwige; Klepin, Heidi D.; Hosseinzadeh, Keyanoosh; Clark, Clancy; Cameron, Amy; Leyendecker, John; D'Agostino, Ralph; Topaloglu, Umit; Boteju, Lakmal W.; Boteju, Asela R.; Shorr, Rob; Zachar, Zuzana; Bingham, Paul M.; Ahmed, Tamjeed; Crane, Sandrine; Shah, Riddhishkumar; Migliano, John J.; Pardee, Timothy S.; Miller, Lance; Hawkins, Gregory; Jin, Guangxu; Zhang, Wei; Pasche, Boris.

In: The Lancet Oncology, Vol. 18, No. 6, 01.06.2017, p. 770-778.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer

T2 - a single-centre, open-label, dose-escalation, phase 1 trial

AU - Alistar, Angela

AU - Morris, Bonny B.

AU - Desnoyer, Rodwige

AU - Klepin, Heidi D.

AU - Hosseinzadeh, Keyanoosh

AU - Clark, Clancy

AU - Cameron, Amy

AU - Leyendecker, John

AU - D'Agostino, Ralph

AU - Topaloglu, Umit

AU - Boteju, Lakmal W.

AU - Boteju, Asela R.

AU - Shorr, Rob

AU - Zachar, Zuzana

AU - Bingham, Paul M.

AU - Ahmed, Tamjeed

AU - Crane, Sandrine

AU - Shah, Riddhishkumar

AU - Migliano, John J.

AU - Pardee, Timothy S.

AU - Miller, Lance

AU - Hawkins, Gregory

AU - Jin, Guangxu

AU - Zhang, Wei

AU - Pasche, Boris

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

AB - Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

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UR - http://www.scopus.com/inward/citedby.url?scp=85019049209&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(17)30314-5

DO - 10.1016/S1470-2045(17)30314-5

M3 - Article

VL - 18

SP - 770

EP - 778

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 6

ER -