Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer

Figures & data

Figure 1. Toca 511 design and mechanism of action: (a) Toca 511 is a retroviral replicating vector (RRV) based on an amphotropic mouse gamma-retrovirus which also encodes an optimized yeast cytosine deaminase (CD) and preferentially infects tumors (LTR: long terminal repeat sequences, gag/pol/env: retroviral structural genes, IRES-CD: transgene expression cassette consisting of internal ribosome entry site linked to CD gene). (b) Upon 5-FC administration, optimized CD metabolizes the antifungal prodrug Toca FC (a proprietary formulation of 5-FC) to the active anticancer drug 5-FU directly within infected cancer cells. (c) Illustration of mechanism of action of Toca 511 and Toca FC causing antitumor immune activation via the tumor microenvironment: (1) Gamma-retrovirus Toca 511 selectively infects tumor, persists, and further spreads through tumor while delivering the CD gene; (2) Toca FC prodrug locally converts to 5-FU chemotherapeutic drug within the tumor, killing cancer cells and resulting in activation of antigen-presenting cells and T cell priming; (3) ‘Bystander effect’ of locally generated intratumoral 5-FU also eliminates adjacent immunosuppressive myeloid cells (myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs)), thereby activating antitumor immunity

Table 1. Survival results from Phase 1 trials of Toca 511/Toca FC therapy in recurrent high-grade glioma patients (www.clinicaltrials.gov: NCT01156584, NCT01470794, NCT01985256)

ClinicalTrials.gov Identifier	NCT01156584	NCT01470794	NCT01985256
Route of vector adminstration	Intratumoral injection	Post-resection tumor cavity wall injection	Intravenous injection
Number of patients in study	24	23	17
mOS, months (95% CI)	11.2 (7.1, 13.8)	14.4 (11.3, 28.1)	13.6 (5.8, 19.7)

mOS, median overall survival.

Table 2. Objective Response, durableresponse and clinical benefit rates in the Phase 1 resection trial (NCT01470794)

Response category ^a	All patients^b n = 53 (%)	Phase 3-eligible subgroup n = 23 (%)
Complete response	6 (11.3) ^c	5 (21.7)
Partial response	0	0
Stable disease	10 (18.9)	5 (21.7)
Progressive disease	37 (69.8)	13 (56.6)
Clinical benefit (CR+PR+SD ≥ 6 weeks)	16 (30.2)	10 (43.5)
Durable response (PR or CR ≥ 24 weeks)	6 (11.3)	5 (21.7)
Median duration of follow-up for responders (months)	35.1^d (range: 9.2–44.9)	35.7^d (range: 14.1–44.9)

^aDetermined by independent radiology review (IRR) using modified MacDonald criteria for all patients, except for a cohort that received Toca 511 and Toca FC and bevacizumab that used modified RANO criteria, taking into account corticosteroid and clinical data.

^bOut of 56 safety evaluable patients, 53 patients who received Toca 511 and Toca FC are efficacy-evaluable.

^cIncludes a patient treated with Toca 511 and Toca FC and bevacizumab who had a CR, which began more than 11.2 months after administration of Toca 511. Because responses in the bevacizumab setting typically occur within a few months of treatment, and even then CRs are rare, the response in this patient is more likely consistent with the immunologic mechanism of Toca 511 and Toca FC therapy.

^dSurvival and responses were ongoing as of this data cut (December 2017).

Figure 2. ‘Swim lane’ representation of data from the Phase 1 resection study in recurrent high-grade glioma patients, higher dose cohorts (‘Phase 3 eligible’): Toca 511 and Toca FC leads to 26% long-term survival and 22% durable complete response (CR) rate. All responses are durable CRs and associated with long-term survival (see Cloughesy et al. 40)

Figure 3. ‘TOCA 5’ Phase 2/3 clinical trial of Toca 511/Toca FC for recurrent high-grade glioma (HGG). (a) Study design of TOCA 5 trial. This was the largest randomized study conducted in the setting of recurrent HGG. GBM: glioblastoma multiforme, AA: anaplastic astrocytoma, IDH1: isocitrate dehydrogenase-1, KPS: Karnofsky Performance Score, SOC: standard of care. (b) Kaplan–Meier plot of overall survival by time from last Temozolomide treatment to randomization (ITT population). (c) Kaplan–Meier plot of overall survival by number of Toca FC cycles in the Phase 2/3 trial (intention-to-treat (ITT) population)

Table 3. No major safety signals with Toca 511 and Toca FC in Phase 3 trial

Most common (≥5%) treatment emergent adverse events (TEAE)			Most common (≥2%) treatment emergent serious adverse events (TESAE)
Grade 3–4 TEAE	Toca 511 and Toca FC (n = 201)	SOC (n = 199)	Grade 3–4 TESAE	Toca 511 and Toca FC (n = 201)	SOC (n = 199)
Aphasia	16 (8.0%)	7 (3.5%)	Brain edema	8 (4%)	2 (1%)
Hemiparesis	15 (7.5%)	5 (2.5%)	Pulmonary embolism	7 (3.5%)	5 (2.5%)
Headache	13 (6.5%)	10 (5%)	Seizure	7 (3.5%)	8 (4%)
Seizure	8 (4.0%)	11 (5.5%)	Hemiparesis	6 (3%)	1 (0.5%)
WBC decrease	0	10 (5.0%)	Headache	5 (2.5%)	0
TEAEs leading to treatment discontinuation	2 (1%)	5 (2.5%)	Vasogenic cerebral edema	4 (2.0%)	0
TEAEs Leading to death	6 (3%)	3 (1.5%)	Fall	4 (2.0%)	1 (0.5%)
No treatment-related aes resulted in death			Subdural hematoma	4 (2.0%)	1 (0.5%)

Figure 4. Overall survival in patient subgroup with two or more recurrences (intention-to-treat population). Left panel: Kaplan–Meier plot of overall survival in the second recurrence subgroup; Toca 511 and Toca FC showed 57% reduction in risk of death (~2X median survival over standard of care (SOC)). HR: hazard ratio, OS: overall survival. Right panel: Key parameters of the Toca 511/Toca FC treatment vs. SOC groups, showing good comparability. KPS: Karnofsky Performance Score, IDH: isocitrate dehydrogenase

Figure 5. Overall survival by tumor histology in patient subgroup with two or more recurrences (intention-to-treat population). Left panel: Kaplan–Meier plot of overall survival in second recurrence subgroup patients with glioblastoma multiforme (GBM). Right panel: Kaplan–Meier plot of overall survival in second recurrence subgroup patients with anaplastic astrocytoma (AA). HR: hazard ratio, OS: overall survival

Table 4. Median number of drug treatments for the intention-to-treat group (Toca FC) and the standard-of-care (SOC) control arm in the Phase 3 trial

	Toca FC prodrug	Standard of care (SOC)
		M_TMZ	TMZ	Lomustine	Bevacizumab
Patients	n = 197	n = 18	n = 31	n = 66	n = 26
Mean number of treatment cycles (SD)	3.4 (3.36)	4.7 (3.80)	4.4 (3.64)	2.3 (1.68)	6.2 (5.49)
Median number of treatment cycles	2	3	3	2	4
Min, Max	1, 21	1, 11	1, 15	1, 7	1, 24

M_TMZ: temozolomide at a dose of 50 mg/m2 once daily continuously

TMZ: temozolomide at an initial dose of 150 mg/m² once daily for 5 consecutive days per 28-day treatment cycle, that may be raised to 200 mg/m² once daily for 5 consecutive days in the following 28-day treatment cycles

Lomustine: single oral dose of 110 mg/m² repeated every 6 weeks

Bevacizumab: 10 mg/kg by intravenous (IV) infusion every 2 weeks; 1 cycle is defined by 2 courses of bevacizumab

Cloughesy TF, Landolfi J, Vogelbaum MA, et al. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. Neuro Oncol. 2018;20(10):1383–1392. DOI:https://doi.org/10.1093/neuonc/noy075.

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