ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886

A. Dean; T. J. Price; K. Sjoquist; N. Aryal; J. Mumford; F. Day; S. Yip; A. Walsh; D. Siu; C. Jackson; S. Padinharakam; B. Lee; M. Burge; J. Lynam; N. Tebbutt; Z. W. J. Wong; L. L. Lam; J. Lee; L. Chantrill; M. Harris

doi:10.1016/j.annonc.2022.10.167

Abstract

Background: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease. Standard first line chemotherapy is with gemcitabine and nab-paclitaxel, or FOLFIRINOX and median overall survival (OS) remains poor, under 12 months. The dense PDAC stroma acts as a barrier to drug delivery. CEND-1 is a novel cyclic tumor-penetrating peptide iRGD (internalizing arginylglycylaspartic acid) that may improve drug delivery by activating an endocytic/exocytic transport pathway by binding αvB3/5-integrins and downstream neuropilin-1. In the Phase 1/1b study, 29 participants with untreated metastatic PDAC were administered CEND-1 at doses of 0.2, 0.8, 1.6, and 3.2 mg/kg. No dose limiting toxicities were reported and safety was comparable to nab-paclitaxel and gemcitabine. 3.2mg/kg CEND-1 is used in ASCEND as this dose had the best objective response rate (ORR) of 61.5%.
Trial design: Multicenter Phase II double-blind placebo controlled randomized trial evaluating activity and safety of CEND-1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Endpoints: (1) PFS; (2) ORR (RECIST 1.1), safety (CTCAE v5.0), OS, patient reported outcomes (PRO; EORTC-QLQ-C30, QLQ-PAN26); (3) predictive/prognostic biomarkers via archival tissue. Sample size 125 for 2:1 randomization (CEND-1:placebo) calculated for 80% power and 95% confidence to exclude uninteresting 6 month PFS of 47% (control) in favor of 61.2% (CEND-1). Recruitment commenced on 13th April 2022 with anticipated accrual time 18 months; 18 months follow up. 7 patients have been recruited as of 12th July 2022. Intervention arm will receive CEND-1 (3.2mg/kg), gemcitabine (1000mg/m2), nab-paclitaxel (125mg/m2) Days 1, 8, 15 of 28 day cycle until disease progression (PD). CEND-1 replaced with placebo for control arm. Patient to complete PRO assessment at baseline then every 8 weeks until PD.
Clinical trial identification: NHMRC CTC Protocol Number: CTC0304, AGITG Protocol Number: AG0121PC, Release Date: 29 March 2022.

Original language	English
Article number	131TiP
Pages (from-to)	S1483
Number of pages	1
Journal	Annals of Oncology
Volume	33
Issue number	Supplement 9
DOIs	https://doi.org/10.1016/j.annonc.2022.10.167
Publication status	Published - Nov 2022
Externally published	Yes
Event	European Society for Medical Oncology (ESMO) Asia Congress 2022 - Singapore, Singapore Duration: 2 Dec 2022 → 4 Dec 2022

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Dean, A., Price, T. J., Sjoquist, K., Aryal, N., Mumford, J., Day, F., Yip, S., Walsh, A., Siu, D., Jackson, C., Padinharakam, S., Lee, B., Burge, M., Lynam, J., Tebbutt, N., Wong, Z. W. J., Lam, L. L., Lee, J., Chantrill, L., & Harris, M. (2022). ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886. Annals of Oncology, 33(Supplement 9), S1483. Article 131TiP. https://doi.org/10.1016/j.annonc.2022.10.167

@article{2f40dbdf0c884965916dd3e6fd556e03,

title = "ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886",

abstract = "Background: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease. Standard first line chemotherapy is with gemcitabine and nab-paclitaxel, or FOLFIRINOX and median overall survival (OS) remains poor, under 12 months. The dense PDAC stroma acts as a barrier to drug delivery. CEND-1 is a novel cyclic tumor-penetrating peptide iRGD (internalizing arginylglycylaspartic acid) that may improve drug delivery by activating an endocytic/exocytic transport pathway by binding αvB3/5-integrins and downstream neuropilin-1. In the Phase 1/1b study, 29 participants with untreated metastatic PDAC were administered CEND-1 at doses of 0.2, 0.8, 1.6, and 3.2 mg/kg. No dose limiting toxicities were reported and safety was comparable to nab-paclitaxel and gemcitabine. 3.2mg/kg CEND-1 is used in ASCEND as this dose had the best objective response rate (ORR) of 61.5\%. Trial design: Multicenter Phase II double-blind placebo controlled randomized trial evaluating activity and safety of CEND-1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Endpoints: (1) PFS; (2) ORR (RECIST 1.1), safety (CTCAE v5.0), OS, patient reported outcomes (PRO; EORTC-QLQ-C30, QLQ-PAN26); (3) predictive/prognostic biomarkers via archival tissue. Sample size 125 for 2:1 randomization (CEND-1:placebo) calculated for 80\% power and 95\% confidence to exclude uninteresting 6 month PFS of 47\% (control) in favor of 61.2\% (CEND-1). Recruitment commenced on 13th April 2022 with anticipated accrual time 18 months; 18 months follow up. 7 patients have been recruited as of 12th July 2022. Intervention arm will receive CEND-1 (3.2mg/kg), gemcitabine (1000mg/m2), nab-paclitaxel (125mg/m2) Days 1, 8, 15 of 28 day cycle until disease progression (PD). CEND-1 replaced with placebo for control arm. Patient to complete PRO assessment at baseline then every 8 weeks until PD. Clinical trial identification: NHMRC CTC Protocol Number: CTC0304, AGITG Protocol Number: AG0121PC, Release Date: 29 March 2022.",

author = "A. Dean and Price, \{T. J.\} and K. Sjoquist and N. Aryal and J. Mumford and F. Day and S. Yip and A. Walsh and D. Siu and C. Jackson and S. Padinharakam and B. Lee and M. Burge and J. Lynam and N. Tebbutt and Wong, \{Z. W. J.\} and Lam, \{L. L.\} and J. Lee and L. Chantrill and M. Harris",

year = "2022",

month = nov,

doi = "10.1016/j.annonc.2022.10.167",

language = "English",

volume = "33",

pages = "S1483",

journal = "Annals of Oncology",

issn = "0923-7534",

publisher = "Elsevier",

number = "Supplement 9",

note = "European Society for Medical Oncology (ESMO) Asia Congress 2022 ; Conference date: 02-12-2022 Through 04-12-2022",

}

Dean, A, Price, TJ, Sjoquist, K, Aryal, N, Mumford, J, Day, F, Yip, S, Walsh, A, Siu, D, Jackson, C, Padinharakam, S, Lee, B, Burge, M, Lynam, J, Tebbutt, N, Wong, ZWJ, Lam, LL, Lee, J, Chantrill, L & Harris, M 2022, 'ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886', Annals of Oncology, vol. 33, no. Supplement 9, 131TiP, pp. S1483. https://doi.org/10.1016/j.annonc.2022.10.167

ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886. / Dean, A.; Price, T. J.; Sjoquist, K. et al.
In: Annals of Oncology, Vol. 33, No. Supplement 9, 131TiP, 11.2022, p. S1483.

Research output: Contribution to journal › Meeting abstract

TY - JOUR

T1 - ASCEND

T2 - European Society for Medical Oncology (ESMO) Asia Congress 2022

AU - Dean, A.

AU - Price, T. J.

AU - Sjoquist, K.

AU - Aryal, N.

AU - Mumford, J.

AU - Day, F.

AU - Yip, S.

AU - Walsh, A.

AU - Siu, D.

AU - Jackson, C.

AU - Padinharakam, S.

AU - Lee, B.

AU - Burge, M.

AU - Lynam, J.

AU - Tebbutt, N.

AU - Wong, Z. W. J.

AU - Lam, L. L.

AU - Lee, J.

AU - Chantrill, L.

AU - Harris, M.

PY - 2022/11

Y1 - 2022/11

N2 - Background: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease. Standard first line chemotherapy is with gemcitabine and nab-paclitaxel, or FOLFIRINOX and median overall survival (OS) remains poor, under 12 months. The dense PDAC stroma acts as a barrier to drug delivery. CEND-1 is a novel cyclic tumor-penetrating peptide iRGD (internalizing arginylglycylaspartic acid) that may improve drug delivery by activating an endocytic/exocytic transport pathway by binding αvB3/5-integrins and downstream neuropilin-1. In the Phase 1/1b study, 29 participants with untreated metastatic PDAC were administered CEND-1 at doses of 0.2, 0.8, 1.6, and 3.2 mg/kg. No dose limiting toxicities were reported and safety was comparable to nab-paclitaxel and gemcitabine. 3.2mg/kg CEND-1 is used in ASCEND as this dose had the best objective response rate (ORR) of 61.5%. Trial design: Multicenter Phase II double-blind placebo controlled randomized trial evaluating activity and safety of CEND-1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Endpoints: (1) PFS; (2) ORR (RECIST 1.1), safety (CTCAE v5.0), OS, patient reported outcomes (PRO; EORTC-QLQ-C30, QLQ-PAN26); (3) predictive/prognostic biomarkers via archival tissue. Sample size 125 for 2:1 randomization (CEND-1:placebo) calculated for 80% power and 95% confidence to exclude uninteresting 6 month PFS of 47% (control) in favor of 61.2% (CEND-1). Recruitment commenced on 13th April 2022 with anticipated accrual time 18 months; 18 months follow up. 7 patients have been recruited as of 12th July 2022. Intervention arm will receive CEND-1 (3.2mg/kg), gemcitabine (1000mg/m2), nab-paclitaxel (125mg/m2) Days 1, 8, 15 of 28 day cycle until disease progression (PD). CEND-1 replaced with placebo for control arm. Patient to complete PRO assessment at baseline then every 8 weeks until PD. Clinical trial identification: NHMRC CTC Protocol Number: CTC0304, AGITG Protocol Number: AG0121PC, Release Date: 29 March 2022.

AB - Background: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with unresectable or metastatic disease. Standard first line chemotherapy is with gemcitabine and nab-paclitaxel, or FOLFIRINOX and median overall survival (OS) remains poor, under 12 months. The dense PDAC stroma acts as a barrier to drug delivery. CEND-1 is a novel cyclic tumor-penetrating peptide iRGD (internalizing arginylglycylaspartic acid) that may improve drug delivery by activating an endocytic/exocytic transport pathway by binding αvB3/5-integrins and downstream neuropilin-1. In the Phase 1/1b study, 29 participants with untreated metastatic PDAC were administered CEND-1 at doses of 0.2, 0.8, 1.6, and 3.2 mg/kg. No dose limiting toxicities were reported and safety was comparable to nab-paclitaxel and gemcitabine. 3.2mg/kg CEND-1 is used in ASCEND as this dose had the best objective response rate (ORR) of 61.5%. Trial design: Multicenter Phase II double-blind placebo controlled randomized trial evaluating activity and safety of CEND-1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Endpoints: (1) PFS; (2) ORR (RECIST 1.1), safety (CTCAE v5.0), OS, patient reported outcomes (PRO; EORTC-QLQ-C30, QLQ-PAN26); (3) predictive/prognostic biomarkers via archival tissue. Sample size 125 for 2:1 randomization (CEND-1:placebo) calculated for 80% power and 95% confidence to exclude uninteresting 6 month PFS of 47% (control) in favor of 61.2% (CEND-1). Recruitment commenced on 13th April 2022 with anticipated accrual time 18 months; 18 months follow up. 7 patients have been recruited as of 12th July 2022. Intervention arm will receive CEND-1 (3.2mg/kg), gemcitabine (1000mg/m2), nab-paclitaxel (125mg/m2) Days 1, 8, 15 of 28 day cycle until disease progression (PD). CEND-1 replaced with placebo for control arm. Patient to complete PRO assessment at baseline then every 8 weeks until PD. Clinical trial identification: NHMRC CTC Protocol Number: CTC0304, AGITG Protocol Number: AG0121PC, Release Date: 29 March 2022.

U2 - 10.1016/j.annonc.2022.10.167

DO - 10.1016/j.annonc.2022.10.167

M3 - Meeting abstract

SN - 0923-7534

VL - 33

SP - S1483

JO - Annals of Oncology

JF - Annals of Oncology

IS - Supplement 9

M1 - 131TiP

Y2 - 2 December 2022 through 4 December 2022

ER -

Dean A, Price TJ, Sjoquist K, Aryal N, Mumford J, Day F et al. ASCEND: Randomized, double-blinded phase II study of gemcitabine and nab-paclitaxel with CEND-1 or placebo in untreated metastatic pancreatic ductal adenocarcinoma - An Australasian Gastro-Intestinal Trials Group (AGITG) trial ACTRN12621001290886. Annals of Oncology. 2022 Nov;33(Supplement 9):S1483. 131TiP. doi: 10.1016/j.annonc.2022.10.167