Temozolomide In Patients Research Articles

417P - Effect of cumulative dose of maintenance temozolomide on overall survival in patients with high grade glia tumours: A single institution analysis

BackgroundStandard of care of high grade glia tumors is represented by concomitant temozolomide (TMZ) and radiotherapy (RT), followed by maintenance TMZ. In clinical practice, administering the full programmed cumulative dose of treatment is often a challenge. The effect of different cumulative doses of maintenance TMZ on median overall survival (mOS) is yet not known. MethodsWe retrospectively analyzed patients with histological diagnosis of high grade glia tumors (91% grade IV, 7% grade III, 2% others) treated at our institution with RT plus concomitant TMZ, followed by maintenance TMZ (according to the trial by Stupp et al.), between February 2012 and April 2019. We planned 6 cycles of maintenance TMZ in patients without MGMT hypermethylation and 12 cycles in those with MGMT hypermethylation. The main objective of our research was to study the effect of cumulative dose of maintenance TMZ on mOS in patients without MGMT hypermethylation. We also focused on time from diagnosis to beginning of chemoradiotherapy and its potential effect on mOS in our whole cohort. We performed statistical analysis with SPSS, using Kaplan-Meier curves. ResultsWe enrolled 114 patients, with median age of 63 years (IQR 54-69 y). MGMT was hypermethylated in 35 (30%) patients, not hypermethylated in 56 (49%) patients, unknown in 24 (21%) patients. In our cohort, mOS was 14 months, in line with previously reported data. In patients without MGMT hypermethylation, mOS was 23,4 months when cumulative dose of maintenance TMZ was>= 4500mg/m2 versus 11 months when cumulative dose was < 4500mg/m2(HR 0,23 [0,10-0,54, CI 95%], p<0,001). When considering our entire cohort, chemoradiotherapy was started in a median of 44 days from diagnosis (IQR 35-56 days); mOS was not statistically different in patients who started therapy over 42 days after diagnosis (HR 0,76 [0,44-1,33, CI 95%], p 0,35). ConclusionsOur study shows that in patients with high grade glia tumors without MGMT hypermethylation a cumulative dose of maintenance TMZ < 4500mg/m2negatively impacts on mOS compared to a cumulative dose of>= 4500mg/m2. Moreover time elapsed from diagnosis to beginning of treatment does not significantly influence mOS. Legal entity responsible for the studyDepartment of Medical Oncology, ASST-Settelaghi, Varese (Italy). FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Evaluate the Safety and Effectiveness of Intranasal Administration of Temozolomide in Patients With Glioblastoma

Evaluate the Safety and Effectiveness of Intranasal Administration of Temozolomide in Patients With Glioblastoma

P14.79 Randomized phase II trial of Tumor Treating Fields plus radiation therapy plus temozolomide compared to radiation therapy plus temozolomide in patients with newly diagnosed glioblastoma

Abstract BACKGROUND In last decade, there were numerous attempts to improve the outcome of patients with glioblastoma (GBM), but even after maximal surgical resection, radiation therapy (RT) and temozolomide (TMZ), followed by maintenance TMZ for 6 months the median OS is 14.6 months. In the EF-14 Phase III trial, the addition of Tumor Treating Fields (TTFields) at 200 kHz to maintenance TMZ increased the median OS to 20.9 months, compared with 16.0 months with maintenance TMZ alone (HR, 0.63; 95% CI, 0.53–0.76; p&lt;0.001). Based on these results, the currently accepted standard of care for newly diagnosed GBM (ndGBM) is surgical resection if safely feasible, followed by RT with concomitant TMZ, and then followed by maintenance TMZ in combination with TTFields. Preclinical investigations have shown a radio-sensitizing effect of TTFields on glioma cells, suggesting synergistic effects between TTFields and radiotherapy. In a pilot study of 10 patients with ndGBM, we demonstrated that there was no increased treatment-related toxicity when TTFields were given in combination with RT/TMZ. The only TTFields-related adverse event was skin toxicity below the arrays. Preliminary progression free survival (PFS) data was encouraging. Based on the results of the pilot study, we designed this prospective, randomized Phase II study to further investigate if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. MATERIAL AND METHODS Following debulking surgery or biopsy, 60 adult patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy of at least 3 months will be randomized 1:1 to either a) RT with concomitant TMZ and TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ in combination with TTFields (experimental arm) up to 24 months; or b) RT with concomitant TMZ alone followed by maintenance TMZ in combination with TTFields (control arm). Exclusion criteria: patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or patients with an implanted electronic device. The primary endpoint is progression free survival at 12 months (PFS12). Treatment with TTFields will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. Grading and severity of all adverse events will be recorded using CTCAE V5.0. The sample size of 60 patients provides 80% power with a two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). It is forecasted to take 24 months to fully recruit. Follow-up will continue for &gt;12 months from recruitment of the last patient.

Capecitabine and Temozolomide in Patients with Advanced Pulmonary Carcinoid Tumours

Background: Temozolomide and capecitabine (CAPTEM) chemotherapy is known to be active in patients with pancreatic neuroendocrine tumours. Objective: This retrospective analysis set out to describe the efficacy and toxicity of CAPTEM in patients with advanced pulmonary carcinoids (PCs). Methods: Patients were included with advanced PC who had been treated with a maximum of 6 cycles of oral temozolomide 200 mg/m² on days 10–14 and capecitabine 750 mg/m² b.i.d. on days 1–14, repeated every 28 days, ­followed by monthly intramuscular injection of octreotide 30 mg long-acting release as maintenance treatment. Results: Of the 33 patients, all with well-differentiated PC, 61% had atypical carcinoid, 36% had Ki-67 index >10% and 42% had ≥3 organs involved by metastasis. CAPTEM was administered as first-line treatment in 42% of patients, and 17% had received prior somatostatin analogue treatment. Six patients (18%) achieved a partial response, 19 (58%) had stable disease and 8 (24%) developed progressive disease. After a median time of follow-up of 34.8 months, median progression-free survival (PFS) was 9.0 months and median overall survival 30.4 months. Median duration of disease response was 21.7 months and median duration of disease control 9.7 months. Patients with multi-organ metastasis had shorter PFS, but only when treated as second or third line with CAPTEM (p = 0.023). Conclusions: CAPTEM induced a modest response and PFS rate, comparable to other studies with temozolomide in patients with advanced PC. The efficacy of CAPTEM should be compared to that of monotherapy with temozolomide in a prospective clinical trial.

The Role of Cytotoxic Chemotherapy in Well-Differentiated Gastroenteropancreatic and Lung Neuroendocrine Tumors.

The treatment landscape of well-differentiated neuroendocrine tumors (NETs) has considerably expanded in recent years, and both somatostatin analogs, radiolabeled somatostatin analogs, everolimus, and sunitinib have been incorporated within the therapeutic armamentarium against these malignancies. Even in the context of multiple treatment options available, cytotoxic chemotherapy plays a pivotal role in the management of pancreatic NETs (panNETs), while its activity in midgut carcinoids and lung NETs is still debated. High response rates, ranging from 30 to 70%, have been consistently reported in studies of panNETs investigating streptozotocin-, temozolomide-, or platinum-based regimens, and an unprecedented prolongation of progression-free survival has been recently demonstrated in a prospective, randomized trial of capecitabine and temozolomide in patients with progressive panNETs. As a general principle, cytotoxic chemotherapy appears particularly appropriate in patients with bulky, symptomatic, or rapidly progressing tumors, especially of pancreatic origin, or in the salvage setting of NET patients who have failed alternative therapeutic options. Emerging evidence has also shown the potential efficacy of induction chemotherapy in patients with locally advanced or oligometastatic panNET, but prospective validation is needed before implementation of this approach in routine clinical practice. At present, there is no consensus on adjuvant therapy in pulmonary NETs, and differences between guideline recommendations at this regard mainly stem from the lack of high-level evidence. In the future, the identification of molecular biomarkers of response to chemotherapy might allow better patient preselection, thus leading to improved outcomes.

Abstract CT198: Expansion of Phase I/II study of olaparib and temozolomide in patients with relapsed small cell lung cancer (SCLC) and co-clinical trial in patient-derived xenografts (PDXs) for biomarker discovery

Abstract Background: SCLC is an aggressive high-grade neuroendocrine malignancy. While SCLC is often highly sensitive to first line etoposide/platinum (EP), response rates to second line cytotoxic chemotherapy range ~10-30%. Inhibition of poly(ADP-ribose) polymerase (PARP) by olaparib (O) has shown activity in SCLC in preclinical studies, and may synergize with the alkylating agent temozolomide (T). We previously reported a confirmed objective response rate (ORR) of 34.5% among an initial 30-patient SCLC cohort treated with combination OT in a Phase I/II trial (Farago et al., ASCO 2018). Here we provide analysis after further expansion to a total of 50 patients (pts). Methods: Eligibility criteria included histologically/cytologically confirmed incurable SCLC which had progressed following ≥ 1 platinum-based chemotherapy. O (tablet formulation) and T were administered orally on days 1-7 of 21-day cycles, with a recommended phase 2 dose (RP2D) of O 200 mg BID and T 75 mg/m2 QD. Response assessments were performed every 6 weeks. The primary endpoint was objective response rate (ORR). PDXs were generated from a subset of patients prior to OT and at progression, and OT and EP activity were assessed in vivo in a panel of 32 PDXs in a co-clinical trial. Whole transcriptome expression analysis using RNA sequencing was performed in 31 models to identify candidate biomarkers of sensitivity and resistance, and lead candidates were further interrogated using immunoblotting and immunohistochemistry. Results: Among 50 enrolled pts, the median (m) age was 63 (range 39-85), m number of prior therapies was 2 (range 1-7), 40% were male, and 72% were platinum sensitive. The confirmed ORR was 41.7%. After a m follow up of 7.1 months (mo) among 22 surviving patients, the m progression-free survival (PFS) was 4.2 mo, m overall survival (OS) was 8.5 mo, and m duration of response (DoR) was 4.3 mo. The ORR among platinum-sensitive and platinum-resistant pts was 47.1% and 28.6%, respectively, with no significant differences in mPFS, mOS or mDOR. The most common grade 3/4 treatment related adverse events were neutropenia (38%), anemia (28%) and thrombocytopenia (26%). Among 41 pts treated at the RP2D, dose reductions occurred in 44% overall and 64% of those who received at least 3 cycles. OT activity was further assessed in SCLC PDXs. The efficacy of OT in PDXs derived from 4 patients on the trial mirrored that seen in the patients. Across a panel of 32 PDXs, sensitivity to OT only modestly correlated with sensitivity to EP (Pearson r=0.50 for best response and r=0.48 for time to progression). Candidate biomarkers for sensitivity and resistance to OT were identified in PDX models and validated in patient samples, and will be presented. Conclusions: OT is shows promising clinical activity in relapsed SCLC. A co-clinical trial in PDXs provides a powerful platform for assessment of cross-resistance to other therapies and identification of clinically relevant biomarkers. Clinical trials identifier NCT02446704. Citation Format: Anna F. Farago, Beow Yeap, Yin P. Hung, Marcello Stanzione, Jun Zhong, Sarah Phat, David T. Myers, Robert Morris, Marina Kem, Deepa Rangachari, David Barbie, Subba R. Digumarthy, Lecia V. Sequist, Aaron N. Hata, Mari Mino-Kenudson, Alice T. Shaw, Nicholas Dyson, Benjamin J. Drapkin. Expansion of Phase I/II study of olaparib and temozolomide in patients with relapsed small cell lung cancer (SCLC) and co-clinical trial in patient-derived xenografts (PDXs) for biomarker discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT198.

Abstract CT203: Randomized Phase II trial of Tumor Treating Fields plus radiation therapy plus temozolamide compared to radiation therapy plus temozolomide in patients with newly diagnosed glioblastoma

Abstract Background: Despite attempts to improve the outcome of patients with glioblastoma (GBM), the 3-year survival of patients treated with maximal surgical resection, radiation therapy (RT) and temozolomide (TMZ), followed by maintenance TMZ for 6 months is only 6% with a median OS of 14.6 months. In the EF-14 Phase III trial, the addition of Tumor treating fields (TTFields) at 200 kHz to maintenance TMZ increased the median OS to 20.9 months, compared with 16.0 months with maintenance TMZ alone (HR, 0.63; 95% CI, 0.53-0.76; p&amp;lt; 0.001). Based on these results, the currently accepted standard of care for newly diagnosed GBM (ndGBM) is surgical resection if safely feasible, followed by RT with concomitant TMZ, and then followed by maintenance TMZ in combination with TTFields. Preclinical investigations have confirmed a radio-sensitizing effect of TTFields on glioma cells, suggesting that TTFields given in combination with RT may have a synergistic effect. In a pilot study of 10 patients with ndGBM, we demonstrated that there was no increased treatment-related toxicity when TTFields were given in combination with RT/TMZ. The only TTFields-related adverse event was skin toxicity below the arrays. Preliminary progression free survival (PFS) data was encouraging. Based on the results of the pilot study, we designed this prospective, randomized Phase II study to further investigate if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. Methods: Following debulking surgery or biopsy, 60 adult patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy of at least 3 months will be randomized 1:1 to either i) RT with concomitant TMZ and TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ in combination with TTFields (experimental arm) up to 24 months; or ii) RT with concomitant TMZ alone followed by maintenance TMZ in combination with TTFields (control arm). Patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or patients with an implanted electronic device will be excluded. The primary endpoint is the rate of progression free survival at 12 months (PFS12). Treatment with TTF will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. Grading and severity of all adverse events will be recorded using CTCAE V5.0. The sample size of 60 patients provides 80% power with a two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). It is forecasted to take 24 months to fully recruit. Follow-up will continue for &amp;gt;12 months from recruitment of the last patient. Citation Format: Rachel Grossman, Dror Limon, Felix Bokstein, Carmit Ben Harosh, Zvi Ram. Randomized Phase II trial of Tumor Treating Fields plus radiation therapy plus temozolamide compared to radiation therapy plus temozolomide in patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT203.

Abstract LB-293: A Phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed metastatic colorectal carcinoma

Abstract Background: The base excisional repair (BER) pathway plays an important role in the development of resistance to alkylating agents. TRC102 (methoxyamine HCL) inhibits BER by binding apurinic/apyrimidinic sites, which increases temozolomide (TMZ)-induced DNA strand breaks and apoptosis. We conducted a multihistology phase I/II trial of TRC102 in combination with TMZ in patients (pts) with refractory solid tumors (NCT01851369); here we report the clinical activity of this combination in the phase II refractory colorectal carcinoma (CRC) cohort. The phase I portion of the study demonstrated anemia to be the major dose limiting toxicity of this combination; the recommended phase II doses (RP2D) for the combination were: 125 mg TRC 102 + 150 mg/m2 TMZ (PO, D1-5 of 28-day cycles). The expanded phase II trial utilized a 3-arm Simon 2-stage design based on objective responses documented during the phase I portion of the study (CRC, NSCLC, and granulosa cell ovarian cancer). Methods: Phase II pts were treated at the RP2D, except that pts with BSA &amp;lt; 1.6 m2 received 100 mg of TRC102. Eligibility for the CRC cohort included pts with recurrent, metastatic, histologically confirmed colorectal adenocarcinoma after ≥ 2 lines of therapy, adequate organ function, and an ECOG performance status (PS) ≤ 1. Overall response rate (ORR) was defined as a partial response (PR) or a complete response (CR), per RECIST 1.1 criteria. Results: During the phase I trial, one pt with KRAS mutant CRC experienced a sustained PR of 21 cycles (maximum 70% decrease by RECIST). This pt decided to stop treatment due to travel constraints, but at 17 months off treatment had not progressed. Based on this response, 16 pts were enrolled in the CRC cohort of the phase II trial (3 rectal, 13 colon), all heavily pretreated (median: 6 lines of prior therapy, range: 3-14). Median pt age was 64 years (range: 46-80 years); all had an ECOG PS of 1. Median time on study was 2 cycles (range: 1 to 5 cycles) including 5 pts who came off study for early clinical progression. ORR for this cohort was 6% (1 PR). Nine pts had KRAS mutant disease, including the partial responder, who also was the only pt (of the 10 tested by tumor IHC) with MGMT-negative disease. Grade 3 and 4 protocol treatment-related toxicities included thrombocytopenia (2 pts), hemolysis (1 pt), and diarrhea (1 pt). No pts discontinued the protocol because of toxicity and only 1 pt required dose reduction (thrombocytopenia). Conclusions: Despite a promising phase I result from a pt with CRC, a phase II study of combined TRC102 and TMZ treatment in patients with metastatic colon or rectal adenocarcinoma displayed an ORR of 6%. Assessing tumor MGMT status may help identify pts who could benefit from this combination and pharmacodynamic studies are underway to assess drug activity in responding and non-responding patients. Supported in part by NCI Contract HHSN261200800001E. Citation Format: Geraldine OSullivan Coyne, Cecilia Monge Bonilla, Jennifer Zlott, Naoko Takebe, Robert Meehan, Lamin Juwara, Richard Piekarz, Laurence Rubinstein, Deborah F. Wilsker, Robert J. Kinders, Ralph E. Parchment, Shahanawaz Jiwani, Shivaani Kumar, James H. Doroshow, Alice P. Chen. A Phase II trial of TRC102 (methoxyamine HCl) in combination with temozolomide in patients with relapsed metastatic colorectal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-293.

Abstract 4771: The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose

Abstract Background: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU). The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently being evaluated in a randomized phase III clinical trial for recurrent high grade glioma (glioblastoma (GBM) and anaplastic astrocytoma) (NCT02414165, Toca 5). Temozolomide (TMZ), in combination with radiation therapy, is the standard of care used for first-line chemotherapy treatment of patients with GBM, the most common and aggressive form of primary brain cancer. Previously, we have shown that: (1) Toca 511/5-FC treatment provides durable response in a syngeneic murine glioma model and supports anti-tumor immune memory; (2) The combination of TMZ and Toca 511/5-FC had synergistic efficacy in a TMZ-sensitive human glioma nude mouse model; (3) TMZ did not inhibit the efficacy of Toca 511/5-FC in a TMZ resistant murine glioma syngeneic model; (4) Toca 511/5-FC caused significant radiosensitization in a radioresistant murine glioma model. Results: To assess the interaction of TMZ with escalating doses of Toca 511 (as defined by percent of tumor transduction by RRV), an orthotopic TMZ-resistant murine glioma model, Tu-2449, was utilized. These results show that moderate levels of tumor transduction of Toca 511 (30% - 50%) with 5-FC treatment prolongs survival in the presence of TMZ compared with lower transduction rates (10%). Additionally, mice treated with Toca 511/5-FC and TMZ are being tested for the establishment of anti-tumor immune memory. Conclusion: These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006). Citation Format: Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, Cornelia Bentley. The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4771.

Abstract CT215: Pharmacological inactivation of DNA repair to improve response to immunotherapy: The Arethusa trial in metastatic colorectal cancer

Abstract Background. Metastatic colorectal cancer (CRC) remains mostly incurable, with a survival of about two years only. It has been recently proved that CRCs with genetic defects in the mismatch-repair pathway (MMRd), occurring in 15% of early CRC but only in 5% of metastatic CRC, present with a high tumor mutational burden (TMB), which results in an increased number of neoantigens that can be recognized by the immune system. Indeed, treatment with the anti-programmed cell death protein 1 (PD-1) immune checkpoint inhibitor pembrolizumab or nivolumab is effective in inducing durable objective responses in metastatic CRC MMRd cases. These results are quite remarkable considering that the clinical efficacy was independent from RAS mutations, which constrain the use of targeted treatments and negatively affect prognosis. We recently showed in preclinical models that the pharmacological treatment with temozolomide (TMZ) can induce the inactivation of MMR genes and consequently trigger an increase in immunogenic neoantigens. This suggests that TMZ could be used to prime MMR proficient (MMRp) tumors for response to checkpoint inhibitors. Accordingly, mCRC patients recruited in previous clinical trials where TMZ was administered, acquired alterations of MMR genes upon treatment and showed remarkable increase in TMB at disease progression (PD). We thus designed the ARETHUSA clinical trial to test whether a priming course with TMZ in patients can sensitize mCRC to the anti-PD1 inhibitor pembrolizumab. Methods. Arethusa is a 2-cohorts, phase II trial consisting of three different phases (NCT03519412). During screening-phase, 344 mCRC patients with RAS-extended mutations who failed standard therapies will be tested for MMR status. MMRd CRC patients will proceed directly to trial-phase for immediate pembrolizumab treatment (expected N=14). MMR-proficient (MMRp) patients will be further tested for TMZ sensitivity via assessment of expression of O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry and by promoter methylation analysis. Expected 67 IHC-negative, promoter methylation-positive MMRp patients will thus be eligible for priming-phase and will receive TMZ until PD; TMB will then be assessed on tumor biopsies at resistance. Those patients that will have &amp;gt;20 mutations/megabase (expected N=20) will proceed to that trial-phase and will be treated with pembrolizumab. Overall response rate (primary outcome), Progression Free, and Overall Survival, and treatment related toxicities (secondary outcomes) in MMRp pembrolizumab-treated patients will be estimated. Treatment efficacy and toxicity within pembrolizumab-treated MMRd cohort will be used for comparison. Pre- and post-TMZ biopsies and longitudinal blood and stool collection during priming and trial phases will allow for discovery of predictive molecular markers and for the assessment of integrated tumor and (immune)environment evolution in response to therapy. Citation Format: Silvia Marsoni, Giovanni Germano, Andrea Sartore Bianchi, Filippo Pietrantonio, Nicola Personeni, Alessio Amatu, Emanuela Bonoldi, Emanuele Valtorta, Ludovic Barault, Federica Di Nicolantonio, Filippo de Braud, Lorenza Rimassa, Armando Santoro, Silvia Ghezzi, Andrea Cassingena, Giovanna Marrapese, Loredana Lupica, Giulia Siravegna, Giuseppe Rospo, Cosimo Martino, Luca Lazzari, Paolo Luraghi, Nabil Amirouchene-Angelozzi, Alberto Bardelli, Salvatore Siena. Pharmacological inactivation of DNA repair to improve response to immunotherapy: The Arethusa trial in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT215.

Abstract CT027: Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies and in combination with temozolomide in refractory high-grade astrocytomas

Abstract Background: PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 crosses the blood-brain-barrier. This first-in-human, phase I, multicenter study consists of 2 components. Component 1 evaluated safety, pharmacokinetics (PK), and preliminary clinical activity of single agent PAC-1 in patients with solid tumors or lymphoma. Component 2 combines PAC-1 with temozolomide in patients with refractory high-grade astrocytomas. Methods: Patients with metastatic solid tumors or lymphomas were enrolled in component 1 and patients with refractory high-grade astrocytomas were enrolled in component 2. A modified- Fibonacci dose-escalation 3+3 design was used in both components. The primary objective was to assess maximum tolerated dose (MTD). In component 1, PAC-1 was dosed from 75 to 750 mg daily orally (7 dose levels (DL)) on days 1-21 on 28 days cycle. For all dose cohorts, PAC-1 PK was assessed following doses administered on days 1 and 21 of the first cycle. In component 2, PAC-1 is dosed from 375 to 750 mg daily (up to 4 DL) plus temozolomide orally 150 mg/m2 daily for 5 days. PAC-1 PK was assessed following doses administered on days 7 and 12 and temozolomide PK is performed on Day 12 of the first cycle. Disease assessment was done every 2 cycles. Neurologic and neurocognitive function (NNCF) tests were performed throughout the study due to concern for neurotoxicity. Results: Forty-four patients were enrolled in part 1 and 12 in component 2. In part 1, at DL 1-5 no dose-limiting toxicities (DLTs) were observed. DL 6 was expanded to 6 patients due to one episode of intracranial bleed that occurred during cycle 4 of treatment, assessed initially as possibly related to study drug, but later attributed to new brain metastasis and unrelated to PAC-1. Grade 1 and 2 neurological adverse events such as ataxia and hallucinations were noted in DL 7 and this DL was expanded to 9 patients to assure safety. All other serious adverse events were determined to be unrelated or unlikely related to the study drug. Eleven patients (25%) did not complete 2 cycles of treatment due to rapid progression or withdrawal. Eight patients (18%) had stable disease for at least 2 cycles. One patient (2%) had partial response. In component 2 treating refractory high-grade astrocytomas, 7 patients were accrued to DL 1, and 5 patients to DL 2. No DLT was observed. Nine patients were evaluable for response. Five patients (42 %) had disease progression. Two patients (16%) had stable disease for at least 2 cycles, and two (16%) had partial response. Review of NNCF testing showed a consistent pattern of stable neurologic and cognitive evaluations. The PK data demonstrated satisfactory systemic delivery of PAC-1 following oral administration and acceptable absorption and elimination profiles. Conclusions: Single agent PAC-1 is well tolerated and 750 mg was determined to be the MTD. The combination of PAC-1 plus temozolomide continues to enroll patients in this study. Citation Format: Oana C. Danciu, M. Kelly Nicholas, Matthias Holdhoff, Richard A. Peterson, Neeta Venepalli, Rozina Chowdhery, Paul J. Hergenrother, Theodore M. Tarasow, Arkadiusz Z. Dudek. Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies and in combination with temozolomide in refractory high-grade astrocytomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT027.

Cost-effectiveness of tumor-treating fields added to maintenance temozolomide in patients with glioblastoma: an updated evaluation using a partitioned survival model.

A first cost-effectiveness analysis has raised a strong concern regarding the cost of tumor treatment fields (TTF) added to maintenance temozolomide for patients with glioblastoma. This evaluation was based on effectiveness outcomes from an interim analysis of the pivotal trial, moreover it used a "standard" Markov model. Our objective was to update the cost-effectiveness evaluation using the more flexible potential of the "partitioned survival" model design and using the latest effectiveness data. We developed the model with three mutually exclusive health states: stable disease, progressive disease, and dead. Good fit parametric models were developed for overall survival and progression free survival and these generated clinically plausible extrapolations beyond the observed data. We adopted the perspective of the French national health insurance and used a 20-year time horizon. Results were expressed as cost/life-years (LY) gained (LYG). The base case model generated incremental benefit of 0.604 LY at a cost of €453,848 which, after 4% annual discounting of benefits and costs, yielded an incremental cost effectiveness ratio (ICER) of €510,273/LYG. Using sensitivity analyses and bootstrapping methods results were found to be relatively robust and were only sensitive to TTF device costs and the modelling of overall survival. To achieve an ICER below €100,000/LYG would require a reduction in TTF device cost of approximately 85%. Using a different type of model and updated survival outcomes, our results show TTF remains an intervention that is not cost-effective, which greatly restrains its diffusion to potentially eligible patients.

Phase I study of procaspase activating compound -1 (PAC-1) in combination with temozolomide (TMZ) for the treatment of recurrent malignant glioma.

TPS3164 Background: The caspase family of cysteine proteases play key roles in the initiation and execution of apoptosis. The activation of procaspase-3 to caspase-3 is critical in both the intrinsic and extrinsic apoptotic cascades. Procaspase-3 levels are elevated in many cancers, including glioblastoma (GBM). As a result, caspase-3 levels are abnormally low in these tumors; thus they avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells. PAC-1 has activity against a wide range of cancer cell lines, and in animal models of cancer. PAC-1 crosses the blood brain barrier and has been shown to synergize with TMZ in both canine malignant glioma and meningioma that arise spontaneously. Methods: This Phase I dose escalation study uses a modified- Fibonacci 3+3 design to determine the MTD of PAC-1 when combined with TMZ in patients with recurrent malignant gliomas: anaplastic astrocytoma (AA) and GBM (open to enrollment). Here, we focus on component 2 of the study. Primary objectives: to establish MTD of PAC-1 when combined with a fixed dose of TMZ, tolerability, and toxicity using CTCAE v.4. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary anti-tumor activity correlation with procaspase-3 expression in tumor tissue, radiographic response using the Response Assessment in Neuro-Oncology (RANO) criteria, and neurocognitive function using a validated test battery. Inclusion criteria: diagnosis of recurrent high grade glioma (AA or GBM), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design, Component 2: PAC-1, orally administered, is dosed at 375-650 mg daily (up to 3 dose levels) on days 1-21 of each 28-day cycle. A fixed dose of TMZ, (150 mg/m2), is administered orally, days 8 -12 of each cycle. The study is currently enrolling patients for Component 2. Clinical trial information: NCT02355535.

The role of postradiation temozolomide in patients with newly diagnosed MGMT methylated glioblastoma.

e13530 Background: Standard therapy for patients with newly diagnosed glioblastoma (GBM) includes concurrent temozolomide (TMZ) and radiation (RT) followed by six monthly cycles of adjuvant TMZ. Although TMZ improves survival for MGMT methylated patients, it is unclear if this benefit is from the TMZ given with the radiation, the adjuvant TMZ, or if both are required. This retrospective study was designed to identify MGMT methylated patients who started treatment with near-normal functional status, completed concurrent RT+TMZ, but did not receive adjuvant TMZ to estimate if their survival was significantly less than expected. Methods: We reviewed charts from 190 adults diagnosed with GBM at Johns Hopkins Hospital from 2013 to 2015 recording their Karnofsky Performance Score (KPS), extent of resection, MGMT-methylation and IDH1 mutation status, and treatment records. We selected patients with MGMT-methylated GBM who received concurrent RT+TMZ without adjuvant TMZ for this study. Patients with a KPS &lt; 70 or severe post-radiation complications were excluded. Results: Six patients met the selection criteria. They had a median age of 65 years, average KPS of 80, 2/6 had a gross total resection, and all were IDH1 wildtype. Their overall survival ranged from 17 to &gt; 46 months. Conclusions: The overall survival of these patients who received no adjuvant TMZ is very similar to the median of 23 months reported in the literature for MGMT methylated patients who received adjuvant TMZ. This preliminary data suggests that a prospective study in MGMT methylated patients comparing concurrent RT+TMZ followed by either standard adjuvant TMZ or observation could be considered without placing patients in the experimental arm at excessive risk.[Table: see text]

Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: The ARETHUSA trial.

TPS2659 Background: Metastatic colorectal cancer (CRC) harbouring genetic defects in the mismatch-repair pathway (MMRd) presents with a high tumor mutational burden (TMB), and is highly sensitive to anti–programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We recently showed in preclinical models that the pharmacological treatment with temozolomide (TMZ) can induce the inactivation of MMR genes, and consequently the increase of TMB and immunogenic neoantigens, thus suggesting that TMZ could be used to prime MMR proficient (MMRp) tumors for response to checkpoint inhibitors. Accordingly, mCRC patients recruited in previous clinical trials where TMZ was administered, acquired alterations of MMR genes upon treatment and showed remarkable increase in TMB at disease progression (PD). We thus designed the ARETHUSA clinical trial to test whether a priming course with TMZ in patients can sensitize mCRC to the anti-PD1 inhibitor pembrolizumab. Methods: Arethusa (NCT03519412) is a 2-cohorts, phase II trial consisting of three different phases. In the SCREENING, 348 mCRC RAS-mutated patients will be tested for MMR status. MMRd patients will proceed directly to TRIAL for immediate pembrolizumab treatment (expected 14). MMR-proficient (MMRp) patients will be further tested for expression of O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry and by promoter methylation analysis. IHC-negative, promoter methylation-positive MMRp patients (expected 67) will enter in the PRIMING phase and will be treated with TMZ until PD. TMB will then be assessed on tumor biopsies at resistance. Those patients that will have &gt; 20 mutations/megabase will proceed to TRIAL (expected 20) and will be treated with pembrolizumab. Overall response rate (primary outcome), Progression Free, and Overall Survival, and treatment related toxicities (secondary outcomes) in MMRp pembrolizumab-treated patients will be estimated., while the MMRd cohort will be used for comparison. Tissue biopsies, longitudinal blood and stool collection will be used for discovery of predictive molecular biomarkers and assessment of tumor evolution. Clinical trial information: NCT03519412.

NovoTTF-200A Together With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed GBM

NovoTTF-200A Together With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed GBM

QIM19-128: Improving Oral Chemotherapy Safety in Adult Neuro-Oncology Clinics

Background: The development of oral chemotherapies (OC) have transformed cancer care for millions of patients. Most patients with brain tumors have temozolomide (TMZ) delivered to their home. While this has improved the patient experience, it presents significant challenges to safety of prescription, administration, and side effect monitoring. While there are guidelines for documentation, there is not a best practices system for managing OC. This project identified areas of latent errors and implemented a standardized process for OC management. Methods: After review of the literature, we developed a process map for our institution’s practice and performed hazard analysis. We then evaluated the process at 3 other neuro-oncology practices. Based on these evaluations, changes were implemented at several stages (Table 1). Objective binary measures that could be recorded for every TMZ prescription were collected by chart review of the 6 months prior to process change. These measures were monitored every 2 weeks after process change implementation using run charts. A baseline process mean was calculated for each measure from the 6 months before program implementation. Successful change implementation was defined as 7 consecutive 2-week averages that were continually on one side of the process mean. Results: At the time of this abstract submission, we had successfully reduced refills for OC and increased documentation of dose calculation and dose ordered. There is improvement in independent dose calculation by 2 providers and dedicated chemotherapy teaching visits; however, these have not yet reached criteria for process change. Additionally, oral chemotherapy order sets were created in the electronic medical records system and an on-site specialty pharmacy was added as another safety measure in OC management. Conclusions: This project used published studies and multi-institutional process mapping and hazard analysis to implement a standardized ordering of TMZ for patients with brain tumors. This process can be implemented for OC management in other oncology practices.

Improving survival in molecularly selected glioblastoma

Clinical investigation of novel treatments for glioblastoma has been met with repeated setbacks over the past two decades. Modest, but clinically meaningful, improvement in survival has only been shown for temozolomide 1 Stupp R Mason WP van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005; 352: 987-996 Crossref PubMed Scopus (14754) Google Scholar and tumour-treating fields, 2 Stupp R Taillibert S Kanner A et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017; 318: 2306-2316 Crossref PubMed Scopus (1066) Google Scholar whereas many randomised trials assessing drugs targeted to vascular endothelial growth factor, 3 Gilbert MR Dignam JJ Armstrong TS et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014; 370: 699-708 Crossref PubMed Scopus (1854) Google Scholar , 4 Chinot OL Wick W Mason W et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370: 709-722 Crossref PubMed Scopus (1723) Google Scholar integrins, 5 Stupp R Hegi ME Gorlia T et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071–22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15: 1100-1108 Summary Full Text Full Text PDF PubMed Scopus (669) Google Scholar and epidermal growth factor receptor (EGFR), 6 Weller M Butowski N Tran DD et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017; 18: 1373-1385 Summary Full Text Full Text PDF PubMed Scopus (580) Google Scholar showed that such drugs failed to prolong patient survival. Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA–09): a randomised, open-label, phase 3 trialOur results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. Full-Text PDF

Hypofractionated Radiation Therapy With Temozolomide For Patients With Glioblastoma Multiforme Recursive Partitioning Analyzes Class V and VI

Hypofractionated Radiation Therapy With Temozolomide For Patients With Glioblastoma Multiforme Recursive Partitioning Analyzes Class V and VI

A Phase 2 Trial of Neoadjuvant Temozolomide (TMZ) Followed By Accelerated Hypofractionated Radiation Therapy (AHRT) and TMZ Followed By Adjuvant TMZ in Patients with Newly Diagnosed Glioblastoma (GBM): Long Term Survival and Toxicity Analysis

Purpose: Encouraging results were observed on analysis of a phase II of neoadjuvant temozolomide (TMZ) followed by AHRT and TMZ followed by adjuvant TMZ in patients with newly diagnosed GBM. Here, we report long term outcomes. Fifty patients were accrued: age >18 years, histologically-proven GBM, KPS ≥ 60 and adequate hematologic, renal, and hepatic functions. Three to 4 weeks post-surgery patients started neoadjuvant TMZ for 2 weeks, followed by concomitant AHRT and TMZ followed by adjuvant TMZ. GTV was surgical cavity and/or postoperative contrast-enhancing lesion on MRI. PTV60 included GTV plus 0.5 cm and PTV 40 included GTV plus 2.0 cm. PTV60 received 60 Gy in 20 fractions, while PTV40 received 40 Gy. From March 2009 and July 2013, 50 patients were accrued with a median age of 60 years. MGMT gene promoter was methylated in 21 patients and unmethylated in 27. Gross total and partial resection were performed in 46, and biopsy in 4 patients. With a median follow up of 71 months for patients at risk, median OS is 22 months with PFS of 13.2 months. At 3 and 5 years, actuarial OS was 34% and 23%, respectively. Methylated MGMT gene promoter patients have OS of 57% and 40.9% at 3 and 5 years, respectively compared to 18.5% and 11.1% for unmethylated MGMT. Eleven patients had reoperation for suspected recurrence, 5 were found to have radiation effects with no evidence of recurrence. The actuarial freedom from necrosis is 82.5% at 78 months, with a plateau after 32.9 months. One patient had a grade 5 hematological toxicity without evidence of disease recurrence at time of death. Another patient developed a grade 4 hepatotoxicity which reversed back to normal after discontinuation of TMZ. As of the date of this report, 10 patients are alive at present with ECOG status of 0 in 4, ECOG 1 in 2, ECOG 2 in 3, and ECOG 3 in one patient. Of the 10 patients 7 are not receiving corticosteroids, while 3 are receiving dexamethasone doses varying between 0.5 mg and 4 mg QD. With a longer follow up, the initially observed OS was further confirmed, and compares favorably to OS reported by large clinical trials. The long-term toxicity continues to be monitored closely, especially for this special group of patients with long survival. Laboratory, in-vitro and in-vivo, experiments are currently underway to further understand the molecular basis of the interactions of neoadjuvant TMZ and AHRT. Future plans are to conduct a phase III randomized clinical trial to compare the current approach versus the standard Stupp’s regimen.