Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

Timothy F. Cloughesy; Joseph Landolfi; Michael A. Vogelbaum; Derek Ostertag; James B. Elder; Stephen Bloomfield; Bob Carter; Clark C. Chen; Steven N. Kalkanis; Santosh Kesari; Albert Lai; Ian Y. Lee; Linda M. Liau; Tom Mikkelsen; Phioanh Nghiemphu; David Piccioni; William Accomando; Oscar R. Diago; Daniel J. Hogan; Dawn Gammon; Noriyuki Kasahara; Thian Kheoh; Douglas J. Jolly; Harry E. Gruber; Asha Das; Tobias Walbert

doi:10.1093/neuonc/noy075

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

Timothy F. Cloughesy, Joseph Landolfi, Michael A. Vogelbaum, Derek Ostertag, James B. Elder, Stephen Bloomfield, Bob Carter, Clark C. Chen, Steven N. Kalkanis, Santosh Kesari, Albert Lai, Ian Y. Lee, Linda M. Liau, Tom Mikkelsen, Phioanh Nghiemphu, David Piccioni, William Accomando, Oscar R. Diago, Daniel J. Hogan, Dawn GammonNoriyuki Kasahara, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Asha Das, Tobias Walbert

Neurosurgery

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

Abstract

Background. Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods. In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results. Among 56 patients, durable complete responses were observed. A subgroup was identified based onToca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions. Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

Original language	English (US)
Pages (from-to)	1383-1392
Number of pages	10
Journal	Neuro-Oncology
Volume	20
Issue number	10
DOIs	https://doi.org/10.1093/neuonc/noy075
State	Published - Sep 3 2018

Bibliographical note

Funding Information:
The authors thank the ABC2 Foundation, the National Brain Tumor Society, the American Brain Tumor Association, the Musella Foundation, and Voices Against Brain Cancer for their support and collaborations. N.K. was also supported in part by U01NS059821 from the National Institute of Neurological Diseases and Stroke.

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Keywords

Durable response rate
Gene therapy
Immuno-oncology
Immunotherapy
Recurrent high grade glioma

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/neuonc/noy075

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Cloughesy, T. F., Landolfi, J., Vogelbaum, M. A., Ostertag, D., Elder, J. B., Bloomfield, S., Carter, B., Chen, C. C., Kalkanis, S. N., Kesari, S., Lai, A., Lee, I. Y., Liau, L. M., Mikkelsen, T., Nghiemphu, P., Piccioni, D., Accomando, W., Diago, O. R., Hogan, D. J., ... Walbert, T. (2018). Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro-Oncology, 20(10), 1383-1392. https://doi.org/10.1093/neuonc/noy075

Cloughesy, TF, Landolfi, J, Vogelbaum, MA, Ostertag, D, Elder, JB, Bloomfield, S, Carter, B, Chen, CC, Kalkanis, SN, Kesari, S, Lai, A, Lee, IY, Liau, LM, Mikkelsen, T, Nghiemphu, P, Piccioni, D, Accomando, W, Diago, OR, Hogan, DJ, Gammon, D, Kasahara, N, Kheoh, T, Jolly, DJ, Gruber, HE, Das, A & Walbert, T 2018, 'Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC', Neuro-Oncology, vol. 20, no. 10, pp. 1383-1392. https://doi.org/10.1093/neuonc/noy075

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title = "Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC",

abstract = "Background. Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods. In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results. Among 56 patients, durable complete responses were observed. A subgroup was identified based onToca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions. Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.",

keywords = "Durable response rate, Gene therapy, Immuno-oncology, Immunotherapy, Recurrent high grade glioma",

author = "Cloughesy, {Timothy F.} and Joseph Landolfi and Vogelbaum, {Michael A.} and Derek Ostertag and Elder, {James B.} and Stephen Bloomfield and Bob Carter and Chen, {Clark C.} and Kalkanis, {Steven N.} and Santosh Kesari and Albert Lai and Lee, {Ian Y.} and Liau, {Linda M.} and Tom Mikkelsen and Phioanh Nghiemphu and David Piccioni and William Accomando and Diago, {Oscar R.} and Hogan, {Daniel J.} and Dawn Gammon and Noriyuki Kasahara and Thian Kheoh and Jolly, {Douglas J.} and Gruber, {Harry E.} and Asha Das and Tobias Walbert",

note = "Funding Information: The authors thank the ABC2 Foundation, the National Brain Tumor Society, the American Brain Tumor Association, the Musella Foundation, and Voices Against Brain Cancer for their support and collaborations. N.K. was also supported in part by U01NS059821 from the National Institute of Neurological Diseases and Stroke. Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.",

year = "2018",

month = sep,

day = "3",

doi = "10.1093/neuonc/noy075",

language = "English (US)",

volume = "20",

pages = "1383--1392",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "10",

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TY - JOUR

T1 - Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

AU - Cloughesy, Timothy F.

AU - Landolfi, Joseph

AU - Vogelbaum, Michael A.

AU - Ostertag, Derek

AU - Elder, James B.

AU - Bloomfield, Stephen

AU - Carter, Bob

AU - Chen, Clark C.

AU - Kalkanis, Steven N.

AU - Kesari, Santosh

AU - Lai, Albert

AU - Lee, Ian Y.

AU - Liau, Linda M.

AU - Mikkelsen, Tom

AU - Nghiemphu, Phioanh

AU - Piccioni, David

AU - Accomando, William

AU - Diago, Oscar R.

AU - Hogan, Daniel J.

AU - Gammon, Dawn

AU - Kasahara, Noriyuki

AU - Kheoh, Thian

AU - Jolly, Douglas J.

AU - Gruber, Harry E.

AU - Das, Asha

AU - Walbert, Tobias

N1 - Funding Information: The authors thank the ABC2 Foundation, the National Brain Tumor Society, the American Brain Tumor Association, the Musella Foundation, and Voices Against Brain Cancer for their support and collaborations. N.K. was also supported in part by U01NS059821 from the National Institute of Neurological Diseases and Stroke. Publisher Copyright: © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

PY - 2018/9/3

Y1 - 2018/9/3

N2 - Background. Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods. In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results. Among 56 patients, durable complete responses were observed. A subgroup was identified based onToca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions. Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

AB - Background. Vocimagene amiretrorepvec (Toca 511) is an investigational gamma-retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune-suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods. In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results. Among 56 patients, durable complete responses were observed. A subgroup was identified based onToca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions. Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders.

KW - Durable response rate

KW - Gene therapy

KW - Immuno-oncology

KW - Immunotherapy

KW - Recurrent high grade glioma

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Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC

Abstract

Bibliographical note

Keywords

UN SDGs

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