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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1383-1392
Number of pages10
JournalNeuro-Oncology
Volume20
Issue number10
DOIs
StatePublished - Jan 1 2018

Fingerprint

Glioma
Isocitrate Dehydrogenase
Cytosine Deaminase
Flucytosine
Recurrence
Myeloid Cells
Standard of Care
Fluorouracil
Immunity
Survival
Therapeutics
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Cloughesy, T. F., Landolfi, J., Vogelbaum, M. A., Ostertag, D., Elder, J. B., Bloomfield, S., ... 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

Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. / Cloughesy, Timothy F.; Landolfi, Joseph; Vogelbaum, Michael A.; Ostertag, Derek; Elder, James B.; Bloomfield, Stephen; Carter, Bob; Chen, Clark C.; Kalkanis, Steven N.; Kesari, Santosh; Lai, Albert; Lee, Ian Y.; Liau, Linda M.; Mikkelsen, Tom; Nghiemphu, Phioanh; Piccioni, David; Accomando, William; Diago, Oscar R.; Hogan, Daniel J.; Gammon, Dawn; Kasahara, Noriyuki; Kheoh, Thian; Jolly, Douglas J.; Gruber, Harry E.; Das, Asha; Walbert, Tobias.

In: Neuro-Oncology, Vol. 20, No. 10, 01.01.2018, p. 1383-1392.

Research output: Contribution to journalArticle

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
Cloughesy TF, Landolfi J, Vogelbaum MA, Ostertag D, Elder JB, Bloomfield S et al. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro-Oncology. 2018 Jan 1;20(10):1383-1392. https://doi.org/10.1093/neuonc/noy075
Cloughesy, Timothy F. ; Landolfi, Joseph ; Vogelbaum, Michael A. ; Ostertag, Derek ; Elder, James B. ; Bloomfield, Stephen ; Carter, Bob ; Chen, Clark C. ; Kalkanis, Steven N. ; Kesari, Santosh ; Lai, Albert ; Lee, Ian Y. ; Liau, Linda M. ; Mikkelsen, Tom ; Nghiemphu, Phioanh ; Piccioni, David ; Accomando, William ; Diago, Oscar R. ; Hogan, Daniel J. ; Gammon, Dawn ; Kasahara, Noriyuki ; Kheoh, Thian ; Jolly, Douglas J. ; Gruber, Harry E. ; Das, Asha ; Walbert, Tobias. / Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. In: Neuro-Oncology. 2018 ; Vol. 20, No. 10. pp. 1383-1392.
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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.",
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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

PY - 2018/1/1

Y1 - 2018/1/1

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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