A phase I study of vistusertib (dual mTORC1/2 inhibitor) in patients with previously treated glioblastoma multiforme: a CCTG study

Sarah Lapointe 1,2 & Warren Mason 2 & Mary MacNeil 3 & Craig Harlos 4 & Roger Tsang 5 & Joana Sederias 6 &
H. Artee Luchman 7 & Samuel Weiss 7 & John P. Rossiter 8 & Dongsheng Tu 6 & Lesley Seymour 6 & Martin Smoragiewicz 6

Received: 23 September 2019 /Accepted: 23 October 2019
# Springer Science+Business Media, LLC, part of Springer Nature 2019

Summary
The PI3K/AKT/mTOR pathway activation plays a central role in glioblastoma multiforme (GBM) development and progression, and in resistance to anti-cancer therapies. Inhibition of the PI3K pathway has been shown to sensitize cultured glioma cells and tumor xenografts to the effects of temozolomide (TMZ) and radiation. Vistusertib is an oral inhibitor of mTORC1/2 complexes. The primary objective of this Canadian Cancer Trials Group phase I study was to determine the recommended phase II dose (RP2D) of vistusertib in patients with GBM receiving TMZ at first progression following primary treatment. Vistusertib was administered at a starting dose of 100 mg bid 2 days on/5 days off weekly with TMZ 150 mg/m2 daily for 5 days/28-days cycle. Dose escalation was according to a 3 + 3 design. Secondary objectives included assessment of vistusertib safety and toxicity profile, and preliminary efficacy. 15 patients were enrolled in the study (median age 66 (range 51–77), females 8). Vistusertib 125 mg BID in combination with TMZ 150 mg/m2 daily for 5 days was well tolerated. Vistusertib treatment-related adverse events were generally grade 1–2, with the most frequently reported being fatigue, gastrointestinal symptoms, and rash. Of 13 response evaluable patients, 1 patient (8%) had a partial response ongoing at 7.6 months of follow-up, and 5 patients had stable disease (38%) as best response (median duration 9.6 months, range 3.7-not yet reached). Six-month progression-free survival (PFS) rate was 26.6%. Combination of vistusertib with TMZ in GBM patients at first recurrence demonstrated a favorable safety profile at the tested dose levels.

Keywords Clinical trial . Glioblastoma . Temozolomide . mTOR inhibitor . mTORC2 . AZD2014

Introduction

Glioblastoma multiforme (GBM) is the most common malig-

* Martin Smoragiewicz [email protected]
nant primary brain tumor in adults [1]. The current standard of care for newly diagnosed GBM consists of maximal safe re- section followed by radiotherapy with concurrent and adju-

1

2
Division of Neurology, Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
Division of Neuro-Oncology, Pencer Brain Tumor Center, University Health Network-Princess Margaret Hospital, Toronto, ON, Canada
vant temozolomide (TMZ), an orally administered alkylating agent [2]. Although the addition of TMZ has improved prog- nosis for many patients, most relapse soon after treatment with a 2-year survival rate of only 27% [3], and a 5-year survival

3QEII Health Sciences Centre, Halifax, NS, Canada rate of 5% [1]. At first progression, salvage therapies have
4CancerCare Manitoba, Winnipeg, MB, Canada been largely ineffective and most patients will progress within

5Tom Baker Cancer Center, Calgary, AB, Canada
2 months of recurrence [4], with a median life expectancy after

6

7

8
Canadian Cancer Trials Group, Queen’s University, Kingston, ON K7L3N6, Canada
Arnie Charbonneau Cancer Institute & Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada
tumor progression of approximately 8 to 9 months [4, 5]. Upon relapse, no clear standard-of-care management algo- rithm exists, and new effective therapies are urgently needed.
The PI3K/AKT/mTOR pathway is a crucial player in the development and progression of GBM [6], and there is signif- icant interest to target the pathway therapeutically. Aberrant activation of the PI3K/AKT/mTOR pathway plays a pivotal

role in the regulation of tumor cell survival, proliferation, mo- tility, angiogenesis and metabolism in a variety of cancers, and is believed to be a dominant driver of resistance to anticancer therapies [7–9]. In a majority of patients with GBM, this path- way is dysregulated [6, 10–16], most commonly through PTEN, PIK3CA or PIK3R1 alterations, but also through other receptor tyrosine kinases upstream of PI3K, including the epi- dermal growth factor receptor (EGFR) [6, 11–14]. The dys- regulated activity and aberrant activation of the PI3K pathway further leads to enhanced activity of mTOR, a critical step for cell-cycle progression. mTOR acts through the canonical PI3K pathway via two different complexes (mTORC1 and mTORC2), having distinct binding sites and functions.
Considerable evidence implicates inactivation of the PTEN gene and subsequent activation of the PI3K/AKT/mTOR sig- naling pathway in gliomas, including an association with poor prognosis [17–19] and a target for therapy in preclinical stud- ies [10–12]. In a cell line model, mTORC1 signaling was required for malignant glioma formation [20]. mTORC2, ac- tivated by PI3K, also activates supplemental kinases and plays an important function in cell proliferation and growth [8, 10–12].
Inhibition of this pathway may result in GBM cell death and delayed tumor progression, and is an active area of re- search. Numerous PI3K pathway inhibitors have shown favor- able preclinical results and have been translated into clinical trials in a range of solid tumors and hematologic malignancies, yet, only a small number have reached phase I/II clinical trials for GBM treatment [7, 15]. Hence, although the EGFR and PI3K pathways are among the most deregulated pathways in GBM [6], pharmacological targeting of EGFR, PI3K, AKT, or mTORC1 have so far failed to demonstrate efficacy in clinical trials [5–7, 15, 21].
PI3K inhibitors are generally classified into pan-PI3K, iso- form-selective, and dual PI3K/mTOR inhibitors. Selective in- hibition of mTORC1 activity alone is not sufficient and trig- gers a negative feedback loop that increases AKT activation, thus largely limiting the therapeutic effects of mTOR and PI3K inhibitors [7]. Indeed, prior phase I and phase II clinical trials with selective mTORC1 inhibitors in newly diagnosed or recurrent GBM have so far failed to improve clinical out- comes [5, 15, 22–25]. Therefore, one strategy to overcome this compensatory AKT activation, due to the S6 kinase loop driven by unregulated mTORC2 signaling, is through dual inhibition of mTORC1 and mTORC2. Recent evidence indi- cates that inhibiting mTORC2 and mTORC1 may have the potential to overcome the limitations that single mTORC1 inhibitors have shown so far [15, 16].
In addition to its direct role in promoting tumors’ pro- liferation and survival, the PI3K/AKT/mTOR signaling pathway has been involved in resistance to a number of anticancer therapies [26–29]. Inhibition of PI3K pathway sensitizes cultured glioma cells and tumor xenografts to

the effects of TMZ and radiation [10, 30, 31]. Hence, the key role of the PI3K/AKT/mTOR pathway in the devel- opment, progression, and resistance to anti-cancer thera- pies, strongly supports exploring the combination of the mTORC1/2 inhibitor vistusertib (AZD2014) and TMZ for the treatment of GBM.
In preclinical studies, AZD8055 (a dual mTOR inhibitor that is no longer in clinical development) inhibited AKT/
mTORC2 signaling and tumor growth in orthotopic human xenograft models of GBM, regardless of their EGFR and PTEN mutational status [16]. AZD8055 was synergistic with TMZ and significantly prolonged animal survival, suggesting that dual inhibition of mTORC1/2 may be of benefit in GBM, including the subset of TMZ-resistant GBMs [16]. Further optimization of AZD8055, focused on reducing the rate of metabolism in human hepatocyte incubations, resulted in the development of vistusertib [32]. Vistusertib is a rationally de- signed ATP-competitive potent mTORC1/2 highly selective oral kinase inhibitor targeting both mTORC1 and mTORC2 complexes [32].
A Phase 1 study (NCT01026402) of vistusertib monother- apy in 135 patients with advanced solid tumors demonstrated an acceptable safety profile, consistent with that reported amongst patients receiving other mTOR inhibitors. The max- imum tolerated doses (MTD) were 50 mg PO BID or 100 mg PO OD for continuous dosing, and 125 mg PO BID for inter- mittent dosing (2 days on, 5 days off). We initiated a phase I trial of vistusertib in patients with GBM at first progression who are receiving TMZ re-challenge.

Materials and methods

Study design and patients

The full eligibility criteria can be found at clinicaltrials.gov (NCT02619864). Eligible patients had histologically confirmed GBM with documented radiographic evidence of recurrence/progression after primary treatment. Patients must have received one TMZ regimen as part of initial treatment, discontinued TMZ at least 16 weeks prior to registration, and had not progressed while receiving adjuvant TMZ or radia- tion. Measurable disease according to Revised Assessment in Neuro-Oncology (RANO) criteria [33] was mandated for all patients enrolled from DL3 onwards. .
Dose escalation followed a standard 3 + 3 design. Vistusertib was administered 2 days on/5 days off weekly, starting at 100 mg PO BID in Dose Level (DL) 1, and esca- lated to 125 mg PO BID in DL2 and 3. TMZ was administered at 150 mg/m2 QD for 5 days in 28 day cycles in DL 1 and 2, and escalated to 200 mg/m2 QD in cycle 2 in DL3. No routine premedication or prophylaxis was mandated. Patients who discontinued either vistusertib or TMZ for toxicity related to

that therapy could continue with the other, at the discretion of the investigator.
For patients with a planned resection, there was an optional pharmacodynamic study with single agent vistusertib for 2 days immediately prior to surgery at a fixed dose of 125 mg PO BID (i.e. on days -2, -1, and on morning of day 0 [day of surgery]). After recovery from surgery, patients started within 7–21 days after tumor resection on the main part of the study.
Toxicity was evaluated according to the CTCAE (Common Terminology Criteria for Adverse Events) Version 4.0. Response was evaluated using the RANO criteria [33] every
2cycles. All responses (CR and PR) required confirmation by repeat imaging after 4 weeks from the time at which response criteria were met. Response duration was measured from the time measurement criteria are first met until disease progres- sion. Stable disease duration was measured from the start of therapy until disease progression.
The protocol was approved by the relevant institutional review boards and complied with the principles of good clin- ical practice. Written informed consent was obtained from each patient participating in the study. Vistusertib was sup- plied by AstraZeneca, and financial support provided by grants from the Canadian Cancer Society (grant # 704970) and Terry Fox Research Institute (grant #2009–20).

Definition of dose-limiting toxicity and maximum administered dose

Dose-limiting toxicity (DLT) was defined as any of the fol- lowing drug related adverse events occurring during Cycle 1 up to DL2, and during Cycle 1 or 2 for DL3: grade 2 diarrhea or rash requiring dose hold ≥5 days or dose reduction; ≥ grade
3organ toxicity including QTc prolongation (>500 msec); grade 4 myelosuppression ≥4 days, febrile neutropenia or grade 3 thrombocytopenic bleeding; any grade 4 toxicity; or other toxicities of concern including toxicities requiring ≥14 days hold. Maximum administered dose (MAD) of vistusertib was defined as the dose level at which at least 2/3 or 2/6 patients in a cohort experienced a DLT. The next lower dose below the MAD was declared the recommended phase II dose (RP2D). Patients must have received ≥75% of planned dose to be considered evaluable for toxicity, unless study drug was held or discontinued for toxicity and/or DLT has occurred.

pS6 immunohistochemistry

Archival tissue from all patients and 2 post-resection speci- mens from the pharmacodynamic study were submitted to a central laboratory. Tissue sections were de-paraffinized with xylene and graded alcohols and antigen retrieval was per- formed using 10 mM sodium citrate, pH 6.0.

Immunohistochemistry (IHC) was performed for phospho- S6 Ser S240/244 (1:100; Cell Signaling Technology) (pS6). Staining was visualized with Vectastain Elite mouse IgG or rabbit IgG ABC kits (Vector Laboratories) and DAB (3,30- diaminobenzidine) substrate (Sigma-Aldrich), followed by hematoxylin counterstaining. An Olympus Slide Scanner and OlyVia (Olympus Life Science) software were used to image the stained tissue sections at the University of Calgary Hotchkiss Brain Institute Core Facility. A neuro-pathologist reviewed digitized images of 5 representative tumor regions, and quantified as pS6 positive if any cancer cells showed cytoplasmic staining.

Statistical analyses and endpoints

The primary endpoint of this study was to determine the rec- ommended phase II dose (RP2D) of vistusertib in recurrent/
progressive GBM patients receiving standard TMZ treatment. Secondary objectives included assessment of the safety and toxicity profile of vistusertib in patients receiving standard TMZ treatment, and the efficacy of vistusertib at the RP2D in addition to standard TMZ treatment, including response rate by RANO criteria and 6 months PFS rate. A phase II expansion cohort was planned at the RP2D to evaluate the
6month PFS rate, however, the study was closed early due to slow patient accrual and discontinuation of the vistusertib clinical program.

Results

Patient characteristics

Between December 2016 and October 2018, 15 patients with recurrent GBM were enrolled and treated in this study. At baseline, median age was 66 years, and 8 pa- tients had ECOG 1. One patient (6%) had an IDH-muta- tion, and 7 out of 8 evaluable patients had MGMT promotor methylation. All 15 patients received prior anti- cancer treatment with TMZ and radiotherapy. Median time from discontinuing previous TMZ to enrollment was 15.1 months (range 3.8–44.1 months). Patient char- acteristics are summarized in Table 1.

Dose escalation, toxicity and dose intensity

As of 22 March 2019, the median duration of follow-up was
7months. The median number of vistusertib and TMZ cycles delivered and dose intensity is summarized in Table 2. In DL3, only one patient escalated TMZ to 200 mg/m2 QD in cycle 2 before the trial was closed, and one patient did not escalate due to investigator decision (G1 neutropenia at Day 1 Cycle 2). A minority of patients required dose modifications of either

Table 1 Patients baseline characteristics abnormalities. The biochemical increases in lipase/

Median age, y (range) Gender, n (%)
Female Male
ECOG, n (%) 0
1
Histology glioblastoma IDH-mutation, n (%)
MGMT promotor methylation, n (%) 1p/19q co-deletion, n (%)
Measurable disease, n (%) Prior therapy, n (%)
Radiotherapy
N = 15

66 (51–77)

8 (53) 7 (47)

7(47)
8(53)
15 (100) 1/15 (6) 7/8 (88) 0/3 (0)
14(93)

15(100)
bilirubin resolved with discontinuation of vistusertib, and TMZ was restarted 25 days later. One patient in DL2 developed G3 muscle weakness in cycle 1 that was deemed probably related to vistusertib. The patient also had objective progressive disease at the end of cycle 1 and was transferred to a palliative care unit. Three patients were registered to DL3. Although no DLTs were observed at this level, only one patient escalated TMZ to 200 mg/
m2 in cycle 2.
2 patients participated in the optional pharmacodynamic study. Both patients received the vistusertib per protocol, and surgery was not delayed. Both patients started the dose escalation of the main study at 15 and 22 days from surgery. Vistusertib related adverse events were limited to grade 1 nau- sea and vomiting during the pharmacodynamics part of the study.

Temozolomide
Prior chemotherapy regimen, n (%)
15 (100) 15 (100)

Anti-tumor activity

Of 15 patients enrolled, 14 patients had measurable disease for

vistusertib or TMZ. A dose reduction was required for TMZ in 1 patient on DL3, and for vistusertib for 1 patient in DL1. At least one missed dose of vistusertib was required for 3, 2, and 1 patient in DL1, 2, and 3, respectively. 14 patients discontinued study treatment. Reasons for discontinuing vistusertib included objective disease progression (n = 10, 71%), adverse events (n = 3, 21%) and one patient withdrew consent. 1 patient remains on study at 15.4 months.
All 15 patients were evaluable for toxicity (Table 3). Vistusertib treatment-related AEs were generally grade 1– 2, and the most frequently reported vistusertib related AEs were fatigue, mild gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, dry mouth, dysgeusia, dys- pepsia, mucositis oral), and rash. DLTs occurred in a total of 2 patients (13%). One patient in DL1 developed G4 lipase increase in cycle 1, as well as G3 increases in bilirubin and alkaline phosphatase. The patient did not have clinical symptoms of pancreatitis and a CT scan did not show evidence of pancreatitis or other
response assessment using the RANO criteria at baseline; one patient refused MRI re-assessment and came off study. 10 patients discontinued treatment due to progressive disease. The overall response rate was 8% (1 of 13 patients), with a confirmed partial response in cycle 8 in a patient treated at DL2. Duration of response is sustained at 7.6 months and the patient is still on study as of March 2019. Five patients (38%) were noted to have stable disease (4 on DL1 and 1 on DL3) with a median duration of 9.6 months (range 3.7-not yet reached). The 6-month PFS rate was 26.6%.

pS6 expression

Immunohistochemistry analysis of archival tumor tissue dem- onstrated expression of pS6, a marker of phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway activation, in cancer cells in the majority of patients (13/15 patients, 87%). Given the small numbers, there was no clear correlation between pS6 status and anti-tumor activity. In the pharmacodynamic study,

Table 2 Planned and actual dose Intensity

DL
Pts Median Cycles (range)
Planned dose intensity per week
Median actual dose intensity per week (range)
Comments

1AZD2014 6 3 (1–11) 400 mg 370 mg (260–393)
TMZ 3 (1–11) 187.5 mg/m2 185 mg/m2 (184–196)
2AZD2014 6 2 (1–17) 500 mg 472 mg (375–500)
TMZ 2 (1–17) 187.5 mg/m2 190 mg/m2 (186–195)
3AZD2014 3 2 (1–4) 500 mg 500 mg (281–500) -1 patient did not escalate
TMZ to 200 mg/m2 in C2 TMZ 2 (1–4) 187.5 mg/m2 190 mg/m2 (187–233) -1 pt. off study in C1 with PD

Table 3 AZD2014 Related

Adverse Events (%)
AE DL1 (N = 6) DL2 (N = 6) DL3 (N = 3)

All Grades ≥ G3 All Grades ≥ G3 All Grades ≥ G3

Nausea 1 3 2
Vomiting 1 3 1
Dry Mouth 1 1 1
Mucositis 1 1
Fatigue 1 5 2
Dry eye 1
Abdominal pain 1 1
Diarrhea 1 3 1
Dysgeusia 1 1 1
Dyspepsia 1 1
Fever 1
Chills 1
Anorexia 1 1 1
Headache 1
Cough 1 1
Pruritus 1
Dry skin 2
Rash maculo-papular 1 1
Hypophosphatemia 1 1 1
Hyperglycemia 1
Lipase increased 1a
Dysphasia 1
Memory impairment 1
Generalized muscle weakness 1+
Hypertension 1
Thromboembolic event 1
Peripheral motor neuropathy 1
Peripheral sensory neuropathy 1
Depression 1 1
Voice alteration 1
Confusion 1

Only toxicities reported as possibly, probably, or definitely related to AZD2014 are listed
a DLT: C1D23 lipase G4; Bilirubin G3; AST/ALT G1; CT no evidence of pancreatitis or other etiologies +DLT

one patient with expression of pS6 in archival tissue demon- strated no pS6 expression in resected tissue post-vistusertib. The converse was observed in the other patient.

Discussion

Based on promising preclinical data of the dual mTORC1/2 inhibition AZD8055, which showed potential anti-glioma ac- tivity [16], we evaluated a similar agent, vistusertib, in patients with recurrent GBM. To our knowledge, only two dual mTORC1/2 inhibitors have so far been evaluated in clinical

trials for GBM; the phase 1 study of mTORC1/2 inhibitor MLN0128 plus bevacizumab in recurrent GBM (NCT02142803) and our phase 1 study of mTORC1/2 inhib- itor vistusertib plus TMZ in recurrent GBM. This is the first complete report of a dual mTORC1/2 inhibitor in GBM.
Treatment with vistusertib in combination with TMZ dem- onstrated an acceptable safety profile in patients with GBM, consistent with previous clinical studies of mTORC inhibitors [24, 34] and the known toxicities of TMZ [35]. Most toxicities were low grade. This contrasts with the increased toxicity observed from the combination of everolimus, an mTORC1 inhibitor, with standard radiation therapy and TMZ in newly

diagnosed GBM in the recent phase 2 study RTOG 0913 [21]. Based on the results of a prior phase 2 study (EORTC 26082) in newly diagnosed GBM patient with unmethylated MGMT tumor that reported good tolerability of the combination of everolimus with standard radiation therapy [25], the authors of the recently published RTOG 0913 suggested that the in- creased toxicities observed were likely due to the combination of everolimus with TMZ. Consequently, they proposed that targeted agents to the PI3K/AKT/mTOR pathway be prefer- entially used in patients with MGMT unmethylated tumors without concurrent TMZ. In the current study, however, the combination of the dual mTORC1/2 inhibitor vistusertib with standard dose TMZ demonstrated an acceptable toxicity profile.
Moreover, although only one (8%) partial response was noted (and sustained for 7.6 months), prolonged disease sta- bility with vistusertib combined with TMZ was seen in 5 (38%) patients, with a median duration of 9.2 months (range 3.7-not yet reached). This prolonged stability of disease in over a third of our patients is impressive, especially in the setting of recurrent disease. In the recent large phase 3 study in patients with GBM at first progression treated with either lomustine alone or lomustine and bevacizumab, the median PFS was less than 2 months in patients treated with lomustine alone [4]. The six-month PFS (PFS-6) rate in our study was 26.6%, which is comparable to the PFS-6 of lomustine alone [4], and better than the PFS-6 in studies using other mTOR inhibitors (PFS-6 between 2% and 17%) [5, 22, 24, 34]. However, the PFS-6 obtained with the combination of TMZ and vistusertib was less than the reported PFS-6 in patients with first recurrent GBM using different TMZ regimens (PFS- 6 between 30% and 55%) [36]. Although it should be noted that this study was not designed to evaluate efficacy, this sug- gests that vistusertib (and probably mTORC1/2 inhibitors in general) adds limited activity to TMZ in unselected patients with recurrent GBM. The identification of a specific molecu- lar subtype that accurately predicts response to mTOR inhib- itors (either alone or in combination) may be one strategy to achieve therapeutic benefit from these agents in future clinical trials. Development of robust and informative PD markers however remains a challenge [37]. A recent analysis of the PI3K signaling pathway in GBM patients showed that loss of PTEN is highly correlated with activation of AKT, which is significantly correlated with phosphorylation of downstream effectors mTOR, the forkhead transcription factors (FOX01, FOX03a, and FOXO4), and S6. [11] pS6 was the pharmaco- dynamic marker used in the current study.
Based on the acceptable toxicity profile of vistusertib com- bined with TMZ, the potential cytostatic properties of dual mTORC1/2 inhibitor given the prolonged disease stability in a subset of patients, and the preclinical evidence showing synergistic activity of dual mTOR inhibitor with TMZ [16], there may be some benefit in pursuing the use of targeted

agent to this pathway in combination with TMZ, particularly in the subset of TMZ-resistant GBMs.
Unfortunately, the limited data available on MGMT pro- moter methylation did not provide sufficient information to assess a potential link between MGMT status and response to treatment in this study. Other limitations related to the study methodology and experimental design prevent conclusions other than the clear demonstration of the safety of vistusertib in combination with TMZ at the tested dose levels. Due to the small sample size, the limited number of patients participating in the pre-operative pharmacodynamic analyses and the lack of pharmacokinetic analyses incorporated in this study, it is not clear whether this regimen achieved adequate intra- tumoral concentrations sufficient to inhibit the intended PI3K/AKT/mTOR pathway targets. Although, a preclinical study showed intra-tumoral activity of the cousin dual mTORC1/2 inhibitor AZD8055 in brain tumor xenografts [16], future pharmacodynamic trials in patients with surgically accessible recurrent GBM would be required to confirm the sufficient tissue exposure to reduce PI3K/AKT/mTOR signal- ing and impact tumor cell proliferation.
Due to slow accrual and the absence of convincing activity of vistusertib in other cancers, the present study was closed prematurely. Indeed, in the phase II MANTA trial of fulvestrant in combination with vistusertib or everolimus or fulvestrant alone in estrogen receptor-positive advanced or metastatic breast cancer (NCT02216786), adding vistusertib to fulvestrant did not improve PFS [38]. The phase II ZEBRA trial of vistusertib versus everolimus in patients with VEGF- refractory metastatic clear cell renal cancer was stopped early due to lack of efficacy of vistusertib [39]. The poor accrual in this study is likely due to eligibility criteria requiring patients not to have progressed on first line therapy and to be more than 16 weeks out from completing first line treatment.
The current study of vistusertib in combination with TMZ in patients with GBM at first recurrence represents, to the best of our knowledge, the first published clinical trial of a dual mTORC1/2 inhibitor in patient with GBM, and demonstrated a favorable safety profile. Further testing of dual mTORC1/2 inhibitors, or of combinations of an mTOR inhibitor with an additional targeted agent, may be worthy of further investiga- tion in selected patients with GBM.

Conclusion

This phase I study of the dual mTORC1/2 inhibitor vistusertib in combination with TMZ in patients with GBM at first recur- rence demonstrated a favorable safety profile at the tested dose levels. Although only one partial response was noted, prolonged disease stability was seen in 38% of patients. Despite the decision to abandon the development of vistusertib, further strategies utilizing dual mTORC1/2

inhibitors in selected patients with GBM may merit additional evaluation.

Acknowledgments The authors acknowledge support from the Canadian Cancer Society and Terry Fox Research Institute. The authors acknowl- edge Dr. Gregory Cairncross for his leadership heading the TFRI GBM Consortium and support in this collaboration.

Funding Financial support was provided by grants from the Canadian Cancer Society (grant # 704970) and Terry Fox Research Institute (grant # 2009–20). This research was conducted with the support from AstraZeneca Canada Inc., which provided study drug.

Compliance with ethical standards

Conflict of interest Dr. Seymour received funding from AstraZeneca on behalf of CCTG, and holds shares in AstraZeneca. No other authors declared any conflicts of interest.

Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institu- tional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent Informed consent was obtained from all individual participants included in the study.

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