bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)
Authors: Shen Colette , Abdou Yara , Chen Linda , Tan Xianming , Gupta Gaorav , Lynce Filipa , Lobbous Mina , Stringer-Reasor Erica , Anders Carey
Published: November 2024

BACKGROUND

Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response.

METHODS

We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.
CTIM-35. PD-1 BLOCKADE WITH CAMRELIZUMAB IN RELAPSED/REFRACTORY PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Ge Jing-Jing , Li Cheng , Qi Shao-Pei , Kong Chen-Chen , Zhao Chi , Xue Feng-Jun , Zhang Jun-Ping
Published: November 2024

Primary central nervous system lymphoma (PCNSL) are rare extranodal large B-cell lymphomas. There are no standard-of-care treatment options for patients with relapsed and refractory PCNSL and the overall prognosis is poor. We conducted a phase 2 clinical trial to evaluate the efficacy and adverse events of PD-1 antibody camrelizumab in relapsed/refractory PCNSL. Enrolled patients received camrelizumab 200mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR). Here we present results of 20 relapsed PCNSL patients who treated with camrelizumab. Among them,12 were male and 8 were female. The median age was 57 years (range 25-67 years). Fourteen patients were available to evaluate efficacy. After camrelizumab treatment, 4 got complete response (CR), 3 got partial response (PR), 1 got stable disease, and 6 got progressed disease (PD). The ORR was 50%. The median progression-free survival (PFS) was 19.3 weeks (95% CI, 3.1-35.5). 24 week PFS rate was 40%. For the 7 patients who got CR/PR, got a long sustained response, with a median PFS of 93.6 weeks (range 17-211.6+ weeks). One patient developed pseudoprogression 2 months after initiation of treatment. By the last follow-up, 18 patients discontinued treatment (10 PD, 4 complete treatment, 3 withdrawal of informed consent, 1 lost follow-up). Eleven patient got PD. Nine patients received chemotherapy and 5 received radiotherapy after PD. PD-L1 expression, microsatellite stability and mutation burden of the tumors were detected in 9 patients, and all the three factors were not correlated with efficacy. The main drug-related adverse reaction was cutaneous capillary hyperplasia. None of the patients dropped out of the study due to adverse reactions. Our data suggest that camrelizumab is active in relapsed/refractory PCNSL and support further investigation of PD-1 blockade in PCNSL.
CTIM-36. IN-SITU VACCINATION OF BIOPSY-ONLY GBM TUMORS BY TUMOR TREATING FIELDS PLUS ANTI-PD-1 IMMUNOTHERAPY RESULTS IN ROBUST ANTIGEN-SPECIFIC T CELL SELECTION AND EXPANSION, HIGH RESPONSE RATE, AND SIGNIFICANTLY EXTENDED SURVIVAL
Authors: Chen Dongjiang , Le Son , Ghiaseddin Ashley , Manektalia Harshit , Li Ming , O’Dell Adam , Rahman Maryam , Tran David
Published: November 2024

We have recently described a complete in-situ immunizing protocol against GBM using Tumor Treating Fields (TTFields) to activate the DNA sensor-dependent inflammasomes and immunogenic cell death. Here, we report successful in-situ vaccination of patients with newly diagnosed GBM, especially in those with bulky, biopsy-only tumors as compared to those with maximally resected disease, using TTFields together with pembrolizumab, an anti-PD-1 immunotherapy. Patients with biopsy-only tumors displayed a marked improvement in both progression-free survival (27.2m vs 9.6m; HR 0.37, 95%CI 0.16-0.85; P=0.014), overall survival (31.6m vs 18.8m; HR 0.4, 95%CI 0.17-0.92; P=0.023), and response rates (66.6% vs 25%) when compared to those with maximally resected tumors. Using a combination of bulk RNA-seq of enriched T cells and single-cell RNA-seq and TCR clonotyping of tumors and PBMC, we tracked clonal evolution of T cells and confirmed that TTFields’ adaptive immune activation followed a type 1 interferon trajectory (T1IFN) specifically through the DC compartment in patients with biopsy-only tumor. From DC, the T1IFN pathway engaged the adaptive immune system, highly correlated with T cell activation (Pearson r=0.81; P=0.000027), and strongly predicted for extended survival (HR 0.3; P=0.034). Importantly, we discovered the adaptive replacement of expanded T cell clones induced by TTFields and enhanced by pembrolizumab predicted for prolonged survival (P=0.031), leading to sustained T cell activation (Pearson r=0.72; P=0.0018) and robust generation of central memory CD4+ and CD8+ T cells, especially in responders with biopsy-only tumors. In recurrent tumors, the PD-1/PD-L1 axis was suppressed, while concurrent upregulation of alternative immune checkpoints was observed in the periphery and TME. This was coupled with ineffective compensatory T cell activation, suggesting potential mechanisms of resistance. These findings highlight the potent in-situ vaccination effects of TTFields and support its co-application with immune checkpoint inhibitors as a promising strategy for GBM, especially in patients with substantial residual tumor.
CTNI-11. A PHASE 1 OPEN-LABEL STUDY OF BRAF INHIBITOR ABM-1310 IN PATIENTS (PTS) WITH RECURRENT BRAF V600-MUTATED PRIMARY CNS TUMORS
Authors: Li Wenbin , Kang Zhuang , Li Shenglan , Chen Feng , Zhang Botao , Huang Mengqian , Yang Zhongyuan , Chen Chen , Yang Zane
Published: November 2024

BACKGROUND

ABM-1310 is a blood-brain barrier penetrant BRAF inhibitor. Here we report interim results from our phase 1 study of ABM-1310.

METHODS

This is a dose-escalation plus expansions trial for adult pts with BRAF V600-mutated primary CNS tumors. In the dose-escalation, ABM-1310 is given at 150 or 200 mg twice a day (bid). In the expansion, ABM-1310 150 mg bid is administered. Study objectives include patient safety, maximum tolerated dose (MTD), preliminary efficacy and pharmacokinetics (PK). Clinical trial information: NCT05892653.

RESULTS

By May 6, 2024, 15 pts (7 male; median age 39 years old) have been treated. In the dose escalation: 4 pts received ABM-1310 150 mg bid, and another 7-pts received ABM-1310 200 mg bid. In the expansion, all 4 pts were given ABM-1310 at 150 mg bid. Among 14 efficacy evaluable pts, 3 had partial response (PR) (including one each of glioblastoma, WHO grade 2 and 3 pleomorphic xanthoastrocytoma) and 9 pts had stable disease as their best responses. Two pts have PR response for > 8 months and continue study treatment. All pts experienced treatment-related AEs. Common AEs were asymptomatic QT prolongation (n=11) and rash (n=10). Seven pts had grade 3 QT prolongation. There was no drug-related SAE. There was no ABM-1310 related dose limiting toxicity although a few pts had study treatment interruption or dose reduction. One patient discontinued prematurely due to asymptomatic Grade 3 QT prolongation. There were no drug-related deaths. The MTD for ABM-1310 was 200 mg bid, the recommended dose was 150 mg bid. In PK assessment, ABM-1310 drug exposure vs. dosage showed a linear proportional relationship. This trial is ongoing.

CONCLUSIONS

ABM-1310 was generally safe and tolerated. There were no new safety signals. Preliminary efficacy data demonstrate favorable anti-cancer activity in patients with recurrent BRAF V600-mutated primary CNS tumors.
CTNI-19. MYCOPHENOLATE MOFETIL TARGETS GLIOBLASTOMA DE-NOVO PURINE METABOLISM TO OVERCOME CHEMORADIATION RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Umemura Yoshie , Clarke Nathan , Al-Holou Wajd , Elaimy Ameer , Scott Andrew , Leung Denise , Kim Michelle , Ferris Sean , Thomas Jennifer , Heth Jason , Schipper Matthew , Suresh Krithika , Lawrence Theodore , Wahl Daniel
Published: November 2024

Glioblastoma prefer de-novo purine synthesis while normal brain prefers resource-efficient salvage pathway. Mycophenolate mofetil (MMF) disrupts de-novo purine metabolism by inhibiting a key enzyme, IMPDH. The pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma models led to this first-in-human phase 0/1 trial (NCT04477200) to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. Tissues from eight phase 0 recurrent glioblastoma subjects, receiving MMF ranging 500-2000mg BID one-week pre-operatively, were analyzed using mass spectrometry. Both enhancing and non-enhancing tumor yielded >1µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p=0.009). In phase 1 study, adult patients were given MMF ranging 1000-2000mg PO BID using TITE-CRM dosing. Twenty-one recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy) with no dose-limiting toxicities (DLTs). Thirty newly diagnosed glioblastoma patients received MMF one-week prior to and concurrently with chemoradiation, followed by MMF one-day before and during 5 days of each adjuvant temozolomide cycles. In the newly diagnosed cohort, there was no DLT with temozolomide and MMF, however, with both temozolomide and radiation, there were five DLT instances noted at 2000mg BID (G3 hemiparesis, G3 cognitive disturbance, G3 fatigue, G4 thrombocytopenia x2): all were reversible. Interim phase 1 median overall-survival in recurrent MGMT-methylated and unmethylated subjects were 16.1 (N=10) and 6.1 (N=11) months, and in newly diagnosed subjects, 27.2 (N=8) and 14.2 months (N=22) respectively. Median follow ups were 7.4 (recurrent) and 23.2 months (new diagnosis). MMF combined with chemoradiation is reasonably well tolerated in glioblastoma patients with promising evidence of drug accumulation in glioblastoma, effective target engagement and inhibition of purine synthesis, leading to a recommended phase 2 dose of MMF 1500mg BID.
CTNI-25. TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM). RESULTS OF PHASE II CLINICAL STUDY
Authors: Grossman Rachel
Published: November 2024

INTRODUCTION

Tumor-Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cancer cell function and tumor progression via a multimodal mechanism of action. Following the phase 3 pivotal EF-14 study, TTFields therapy concomitant with temozolomide (TMZ) maintenance therapy became approved for newly-diagnosed glioblastoma (ndGBM). Pre-clinical data and pilot clinical studies suggests synergistic effect of concomitant TTFields treatment with radiotherapy (RT).

OBJECTIVE

To assess the efficacy and safety of first line TTFields therapy concomitant with RT/TMZ vs RT/TMZ alone in adult patients with ndGBM. Design: 69 patients with ndGBM and KPS≥70 stratified by MGMT status, extent of resection, and age, were randomized 1:1. The experimental arm received TTFields therapy from the first day of chemoradiation, the control arm started 4 weeks after completion of chemoradiation. Patients continued TTFields therapy until second disease progression or 24months. The primary endpoint was 1-year PFS rate, and secondary endpoints included PFS, OS, and safety. Kaplan-Meier estimates were used to assess whether PFS and OS were improved with first line TTFields therapy/RT/TMZ vs RT/TMZ with delayed TTFields therapy.

RESULTS

Overall, 46 patients received maintenance chemotherapy and TTFields therapy. Mean age was 62 years (range:27–77). One-year PFS rate was 36% and 19% in the experimental and control arms, respectively (p-value=0.10). Median PFS was 9.9 and 5.6 months (HR 0.53, p-value 0.049). Median OS was 25.9 and 17 months (HR 0.85, p-value=0.6). Two-year OS rates were 52% and 31% (p-value 0.07). Among patients with high TTFields usage (≥75%) 2-year OS rates were 78% and 34% (p=0.01).

CONCLUSIONS

The addition of concomitant TTFields to standard treatment with temozolomide and RT for patients with ndGBM appears to be another step in improving the outcome of this patients population. This is further investigated in the large-scale TRIDENT study.
CTNI-31. AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY WITH TARGETED DOSE ESCALATION FOR NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY
Authors: Akbari Hamed , Mohan Suyash , Kazerooni Anahita Fathi , Rathore Saima , Bilello Michel , Sako Chiharu , Garcia Jose , Jiang Cecilia , Liu Fang , Berger Melanie , Brem Steven , Bakas Spyridon , Mamourian Elizabeth , Pepin Abigail , James Paul , Dorsey Jay , Singh Ashish , Parker Drew , Verma Ragini , Cao Quy , Shinohara Russell T , Bagley Stephen J , Desai Arati , O’Rourke Donald M , Nasrallah MacLean , Alonso-Basanta Michelle , Teo Boon-Keng Kevin , Kurtz Goldie , Shukla Gaurav , Lustig Robert A , Davatzikos Christos
Published: November 2024

BACKGROUND

The purpose of this study was to assess the feasibility and effectiveness of AI-guided personalized precision radiation therapy (PPRT) with targeted dose escalation in enhancing outcomes for patients with newly diagnosed glioblastoma.

METHODS

An open-label trial was conducted at the University of Pennsylvania (NCT03477513) from August 2018 to April 2023, enrolling 20 patients with IDH-wildtype glioblastoma who underwent maximal safe resection. They were matched with a contemporaneous cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity score matching (PSM) was employed to select the control group, utilizing one-to-four nearest neighbor matching. One patient was excluded due to concurrent treatment with tumor treating fields (TTFields). The PPRT group received personalized radiation dose escalation to 75 Gy in 30 fractions guided by AI-based predictive modeling of recurrence, along with temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy, 60 Gy in 30 fractions. A previously published and evaluated (retrospectively and prospectively) predictive AI model, which has demonstrated high predictive value for neoplastic cell infiltration and future tumor recurrence using preoperative, multi-parametric MRIs, was utilized.

RESULTS

Median overall survival was 24.3 months in the PPRT-temozolomide group compared to 17.5 months in the standard-of-care treatment group (hazard ratio [HR]=0.30; 95% CI: 0.16-0.57; p<0.001). Excluding two patients with leptomeningeal disease and bone marrow metastasis, the median survival was 35.4 months (HR=0.25; 95% CI: 0.12-0.51; p<0.001).

CONCLUSION

AI-guided PPRT for newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and significantly improved overall survival compared to matched controls receiving standard-of-care treatment. These findings underscore the potential of personalized precision radiation therapy, with focused dose escalation, in improving outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.
CTNI-43. MULTI-CENTER PHASE I STUDY OF CONCURRENT PAXALISIB AND RADIATION THERAPY (RT) IN PATIENTS WITH SOLID TUMOR BRAIN METASTASES (BM) OR LEPTOMENINGEAL METASTASES (LM) HARBORING PI3K PATHWAY ALTERATIONS
Authors: Imber Brandon , Kotecha Rupesh , Blau Kathryn , Halasz Lia , Friend John , Young Robert , Offin Michael , Mitchell Ryan , Diamond Eli , Yang Jonathan
Published: November 2024

INTRODUCTION

Partial or whole brain RT is a standard treatment for solid tumor BM and LM. However, tumors harboring PI3K pathway mutations have poorer CNS control after RT alone. Combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, may overcome radioresistance.

METHODS

This multi-center, phase I trial (NCT04192981) studied concurrent paxalisib with cranial RT (30Gy in 10 fractions) for PI3K pathway-altered BM/LM. Part A was a 3 + 3 dose escalation cohort of paxalisib at 45, 60 or 75mg to establish maximum tolerated dose (MTD). Part B was an expansion at MTD to further validate safety and early efficacy. CNS response was assessed using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.

RESULTS

From 3/2020-2/2024, 21 patients (median age 58y, n=18 with BM, n=10 with breast cancer) were enrolled. PIK3CA mutations were the most common pathway alteration (n=15, 71%) followed by PTEN deletion (n=3, 14%). Part A enrolled 12 patients of which 9 were evaluable (3 did not complete protocol therapy). There were no dose-limiting toxicities (DLTs) at 45mg, and 2 DLTs at 60mg: grade 3 nausea and grade 4 neutropenic enterocolitis. Subsequently, 9 additional patients were enrolled during Part B at MTD of 45mg, of which 1 withdrew consent prior to completion of study interventions. No additional DLTs were observed during Part B. In total, there were 14 evaluable patients who received 45mg/day paxalisib concurrently with RT, two of whom died of intercurrent extracranial progression prior to CNS restaging. Of the remaining 12, there was robust response signal. At 1-month post-treatment, 6/12 (50%) had partial response (PR) and the remaining had stable disease (SD). To date, best CNS response is 67% PR (8/12) and 33% SD (4/12).

CONCLUSIONS

A MTD of 45 mg/day has been confirmed for paxalisib with concurrent brain RT for PI3K pathway-altered BM/LM. Given significant unmet need, this novel therapeutic combination warrants further investigation given promising activity signal.
CTNI-45. PHASE 2 STUDY OF SORAFENIB, VALPROIC ACID, AND SILDENAFIL IN THE TREATMENT OF RECURRENT HIGH-GRADE GLIOMA
Authors: Shah Palak , Poklepovic Andrew , Tombes Mary Beth , Shrader Ellen , Bandyopadhyay Dipankar , Deng Xiaoyan , Roberts Catherine , Ryan Alison , Hudson Daniel , Sankala Heidi , Kmieciak Maciej , Dent Paul , Malkin Mark
Published: November 2024

PURPOSE

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma.

PATIENTS AND METHODS

Eligible patients were 18 years of age and older with an Eastern Cooperative Oncology Group performance status of 0-2 and pathologically confirmed high-grade glioma (WHO grade 3 or 4), with documented CT or MRI progression or recurrence and measurable or evaluable disease. The treatment schedule was a combination of sorafenib, valproic acid, and sildenafil, each agent administered orally, twice daily continuously. A cycle consisted of 4 weeks.

RESULTS

Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRa and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive.

CONCLUSIONS

This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.
CTNI-46. WINDOW-OF-OPPORTUNITY TRIAL OF ULIXERTINIB FOR MAPK-ACTIVATED LOWER GRADE GLIOMAS IN ADULTS
Authors: Majd Nazanin , Kamiya-Matsuoka Carlos , Yuan Ying , Gachimova Evguenia , Wathoo Chetna , Dagher Samir , Chen Melissa , McCutcheon Ian , Slopis John , de Groot John
Published: November 2024

Overexpression of MAPK (Ras-Raf-MEK-ERK) signaling is well known in NF1-associated tumors. MEK inhibition has shown promising results in pediatrics NF1-associated tumors. In addition, we have observed augmented MAPK signaling and anti-tumor activity with MAPK inhibition in preclinical models of CIC-mutated vs. wild-type oligodendroglioma. Ulixertinib is a small molecule inhibitor of ERK that is being developed as a novel anti-cancer drug. A phase I study of ulixertinib in advanced solid malignancies had shown two central nervous system responses. We hypothesized that ulixertinib crosses the blood-brain barrier (BBB) and it will result in improved responses in MAPK-activated lower-grade gliomas in adults (recurrent NF1-mutated gliomas grade 1,2,3 and oligodendrogliomas grade 2,3 which are enriched in CIC-mutation). This is a window-of-opportunity study of ulixertinib in patients ≥18 yo. Twenty patients who are candidates for non-emergent surgical resection will be enrolled (10 in each cohort). Patients will receive neoadjuvant ulixertinib at 600mg BID. Selected patients will undergo CSF collection 1-week after and all will undergo surgical intervention 2-weeks after initiation of ulixertinib. Patients will then continue treatment until disease progression or unacceptable toxicity. Primary endpoints are ulixertinib tumor concentration and tumor/plasma ratio in enhancing and non-enhancing disease. Secondary endpoints include median PFS, overall response rate (ORR) and disease control rate at 12mo, duration of response, time-to-next intervention and time-to-response, safety profile, and ulixertinib CSF and tumor/CSF ratio. Exploratory endpoint includes ORR of plexiform neurofibromas in NF1 patients. To date, 4 patients have been dosed; 3 CIC-mutated oligodendroglioma and 1 NF1-mutated glioma. A fifth patient with NF1-mutated glioma has been consented. Upon collection of tumor tissue on all 5 patients, initial assessment of tumor and CSF drug concentration will be conducted and presented at the conference. Ulixertinib’s ability to cross the BBB could influence what tumor types may be explored for further patient benefit.
CTNI-50. CLINICAL EFFICACY AND PK/PD RESPONSE IN A PHASE 0/2 STUDY OF NIRAPARIB PLUS RADIOTHERAPY FOR NEWLY-DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Sanai Nader , Umemura Yoshie , Margaryan Tigran , Molloy Jennifer , Zhang Hualin , Knight William , Harmon Jocelyn , Hong Amy , Wanebo John , Braun Kelly , Kennedy William R , Garcia Michael , Barani Igor , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: November 2024

BACKGROUND

Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is a PARP1/2-selective inhibitor. This Phase 0/2 study evaluates tumor pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy of niraparib plus fractionated radiotherapy in newly diagnosed, O6-methylguanine methyltransferase (MGMT)-unmethylated glioblastoma (GBM).

METHODS

Newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort 2) following the last dose. Tumor tissue (gadolinium-enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation vs non-irradiated control. A PK response was defined as unbound [niraparib] > 5-fold biochemical IC50 (19 nM) in non-enhancing tumor. Patients with MGMT-unmethylated tumors and a PK response were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by niraparib monotherapy.

RESULTS

All Phase 0 patients (n=46) met the PK threshold. The mean unbound concentrations of niraparib in non-enhancing tumor regions were 335.1 nM (cohort 1; n=43) and 331.9 nM (cohort 2; n=3). Ex vivo PAR suppression was observed in 73% of the patients (24/33). 71.4% patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib and all adverse events resolved without sequelae. At a mean clinical follow-up of 13.4 months, median overall survival was 20.3 months.

CONCLUSIONS

Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue. Accompanying PD effects were observed in tumor tissue, no new safety signals were observed, and clinical outcomes were promising. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT-unmethylated glioblastoma is underway.
CTNI-51. A PHASE 0/1 STUDY OF BDTX-1535 IN RECURRENT GLIOBLASTOMA (GBM) PATIENTS WITH EGFR ALTERATIONS OR FUSIONS
Authors: Sanai Nader , Umemura Yoshie , Karapetyan Vahuni , Margaryan Tigran , Huttenlocher Dylan , Harmon Jocelyn , Hong Amy , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: November 2024

BACKGROUND

Alterations to epidermal growth factor receptor (EGFR) occur frequently in high-grade gliomas (HGG) and are critical to its pathogenesis. This Phase 0/1 study evaluates pharmacokinetic (PK), pharmacodynamic (PD), and clinical response to an ATP-competitive, irreversible EGFR inhibitor, BDTX-1535, in recurrent HGG patients with EGFR alterations and/or fusions.

MATERIALS/METHODS

Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 at 200 mg/daily (cohort 1) or 400 mg/every other day (cohort 2) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (gadolinium (Gd) enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’ was defined as unbound drug concentration above 1 nM and 4.1 nM in Gd non-enhancing tumor in patients with EGFR mutations and amplification, respectively, determined eligibility for Phase 1 therapeutic dosing. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue.

RESULTS

Eleven recurrent HGG patients were enrolled (Arm A, n=11; Arm B, n=0). Mean unbound concentrations of BDTX-1535 in non-enhancing tumor regions were 11.9 nM and 18.8 nM in cohorts 1 and 2, respectively. Eight of nine (88.9%) evaluable patients exceeded the PK threshold and qualified for Phase 1. Suppression of pEGFR and MIB1 was observed in 55% and 67% of patients, respectively. No serious adverse events related to BDTX-1535 were observed. At the time of submission, median PFS and OS have not yet been reached.

CONCLUSIONS

BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in non-enhancing tumor tissue, and is associated with suppression of EGFR signaling. Efficacy data accompanying this PK/PD response will be reported.
CTNI-53. A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): UPDATED EFFICACY RESULTS
Authors: Mellinghoff Ingo K , van den Bent Martin J , Touat Mehdi , Blumenthal Deborah T , Peters Katherine B , Ellingson Benjamin M , Clarke Jennifer L , Mendez Joe , Yust-Katz Shlomit , Mason Warren P , Ducray Francois , Umemura Yoshie , Nabors Burt , Hottinger Andreas F , Arakawa Yoshiki , Sepulveda Juan M , Wick Wolfgang , Soffietti Riccardo , Perry James R , Giglio Pierre , de la Fuente Macarena , Maher Elizabeth A , Tron Adriana E , Zhao Dan , Pandya Shuchi S , Steelman Lori , Hassan Islam , Wen Patrick Y , Cloughesy Timothy F
Published: November 2024

INTRODUCTION

The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral, brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Here, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023).

METHODS

Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (≥12 years; Karnofsky Performance Status ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles.

RESULTS

Overall, 331 patients were randomized (median age: 40.0 years; oligodendroglioma: 172; astrocytoma: 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49), and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged.

CONCLUSIONS

Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.
CTNI-55. A PHASE 0/1B STUDY OF AZD1390 PLUS RADIOTHERAPY IN NEWLY DIAGNOSED, MGMT-UNMETHYLATED AND RECURRENT GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Umemura Yoshie , Desai Siddhi , Margaryan Tigran , Molloy Jennifer , LoCascio Costanza , Elliott Mackenna , Harmon Jocelyn , Hong Amy , Melendez Ernesto Luna , Wanebo John , Braun Kelly , Kennedy William R , Garcia Michael , Yoo Wonsuk , Tovmasyan Artak , Tien An-Chi , Mehta Shwetal
Published: November 2024

BACKGROUND

ATM inhibition is hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair. This Phase 0/1b study evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, a first-in-class ATM inhibitor, in combination with radiation in newly-diagnosed and recurrent GBM patients (NCT05182905).

METHODS

All patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hrs following the final dose (120/300mg for nGBM and 400mg for rGBM). Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. ATM inhibition was assessed via ex vivo tissue radiation, quantifying pRAD50 levels compared to non-radiated control. A PK ‘trigger’ determined eligibility for Phase 1b and patients exceeding the PK threshold (2 nM unbound drug levels in Gd-non-enhancing tumor region) were eligible for therapeutic dosing of AZD1390 plus radiotherapy.

RESULTS

Thirty nGBM patients and twenty-nine rGBM patients were enrolled. Forty-eight out of the forty-nine evaluable patients exceeded the PK threshold and qualified for therapeutic dosing. The mean unbound concentrations of AZD1390 in Gd-nonenhancing tumors of both nGBM and rGBM patients were significantly above the threshold at all dose levels and time intervals. Following 5Gy ex vivo radiation of surgical specimens, pRAD50 expression was significantly suppressed in AZD1390-treated patients compared to untreated controls. To date, 6 MGMT-unmethylated nGBM patients and 15 rGBM patients were enrolled in the Phase 1b component of the study, with median clinical follow-up of 7.0 months. Median PFS and OS have not been reached in the nGBM population. Median OS for rGBM patients was 15.4 months.

CONCLUSION

AZD1390 is well-tolerated in both newly-diagnosed and recurrent GBM patients, achieving pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue, and suppressing radiation-induced increase in pRAD50 levels. These data are the first to demonstrate AZD1390-mediated PD and PK responses in nGBM and rGBM patients. Clinical outcomes data are maturing and will be reported.
CTNI-56. PHASE I STUDY OF VORINOSTAT AND TEMSIROLIMUS IN NEWLY DIAGNOSED OR PROGRESSIVE DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Stitzlein Lea M , Baig Muhammad Usman , Chandra Joya , Mahajan Anita , McGovern Susan L , Paulino Arnold , Andersen Clark R , Gill Jonathan , Von Hertell Leena M , Khatua Soumen , Zaky Wafik
Published: November 2024

BACKGROUND

Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Histone mutation, K27M, and AKT pathway dysregulation play key roles in tumorigenesis. There is no curative treatment with radiation therapy, which currently remains the standard treatment.

METHODS

This is a phase I study of vorinostat and temsirolimus in newly diagnosed (stratum 1) and progressive (stratum 2) DIPG. The primary aims are to determine the safety, maximum tolerated dose, and toxicities (NCT02420613). Stratum 1 received radiation concurrently with vorinostat, followed by vorinostat and temsirolimus for up to 10 cycles. Stratum 2 received vorinostat and temsirolimus for up to 12 cycles. In stratum 1, vorinostat was administered daily at 230 mg/m2. The maintenance phase (both strata) included concurrent vorinostat 230 mg/m2 daily and temsirolimus 25 or 35 mg/m2 (Days 1 and 8).

RESULTS

Six patients were enrolled, three in each stratum. Three of the six patients had confirmed H3 K27M mutations. No dose-limiting toxicity was observed, and most adverse effects were limited to grades 1 or 2, including fatigue, nausea, vomiting, myelosuppression, hyperlipidemia, hyperglycemia, elevated liver enzymes, and creatinine. However, one patient experienced grade 3 leukopenia. Two of the three patients in stratum 1 showed evidence of radiographic response after the chemoradiation phase, of whom one patient had progression-free survival of 12 months and completed the 10 maintenance cycles. All patients at stratum 2 had disease progression with no radiographic response.

CONCLUSION

Overall, the combination of temsirolimus and vorinostat is well tolerated and safe, prompting the need for larger studies to investigate its efficacy. Due to the small number of patients, the study’s findings are limited, and trends in efficacy should be interpreted with caution.
CTNI-58. A PHASE 0/2 TRIAL OF ABEMACICLIB PLUS LY3214996 IN RECURRENT GLIOBLASTOMA
Authors: Sanai Nader , Umemura Yoshie , Chang Yu-Wei , Margaryan Tigran , DeSantis Anita , Elliott Mackenna , Molloy Jennifer , Huttenlocher Dylan , Hook Garry , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak , Mehta Shwetal
Published: November 2024

BACKGROUND

This Phase 0/2 study (NCT04391595) evaluates tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and clinical efficacy of abemaciclib, a CDK4 and 6 inhibitor, plus LY3214996, an ERK 1/2 inhibitor, in recurrent glioblastoma (rGBM).

METHODS

Adult rGBM patients (n=42) with intact RB, >30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib plus LY3214996 prior to a planned resection. Time-escalation cohorts (3-5 and 7-9 hour intervals from last dose to tumor resection) identified the optimal time interval (OTI). Subsequent Phase 0 patients had tumor tissue (gadolinium [Gd]-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma collected at the OTI. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD was compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5 x IC50) was set for each drug. Gd-nonenhancing tumor demonstrating PK response to both drugs qualified patients for the Phase 2 component of the study.

RESULTS

Forty two patients were accrued to Phase 0 and no dose-limiting toxicities were observed. Median unbound concentrations in Gd-nonenhancing tumor regions were 31 nM and 10 nM for abemaciclib and LY3214996, respectively. Tumor RB, RSK phosphorylation, and tumor proliferation (MIB-1) decreased in (47.5%), (25%) and (72.5%) patients, respectively. Nine of the 40 (22.5%) patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), qualifying them for Phase 2. Here, median PFS and median OS were 2.4 and 7.2 months, respectively.

CONCLUSION

Abemaciclib and LY3214996 achieved pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue in 80% and 30% of the patients, respectively. Suppression of the RB pathway and tumor proliferation, but not ERK pathway was observed. Inadequate CNS penetration and tumor PD modulation by LY3214996 contributed to the unremarkable clinical efficacy profile of this drug combination. Targeted ERK inhibition remains an unmet need in experimental GBM therapy.
CTNI-64. TRIAL IN PROGRESS: DIET2TREAT -- A RANDOMIZED MULTICENTER PHASE 2 TRIAL OF A KETOGENIC DIET VS STANDARD DIETARY GUIDANCE IN COMBINATION WITH STANDARD-OF-CARE TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Amaral L J , Gresham Gillian , Butowski Nicholas , Peters Katherine , Sharma Akanksha , Fonkem Ekokobe , Chi Jen-Tsan , Lin Pao-Hwa , Kesari Santosh , Shiao Stephen , Tighiouart Mourad , You Sungyong , Rudnick Jeremy , Freedland Stephen , Hu Jethro
Published: November 2024

BACKGROUND

Many glioblastoma (GBM) patients inquire about the potential therapeutic benefits of a high fat / low carbohydrate ketogenic diet (KD). Preclinical models and early-phase trials have shown encouraging results, but definitive evidence of clinical efficacy is lacking.

METHODS

We are conducting a multicenter randomized controlled phase 2 clinical trial (NCT05708352) of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients receive standard-of-care chemoradiation. Inclusion criteria: newly diagnosed GBM, age ≥ 18 years, Karnofsky Performance Status ≥ 70. Exclusion criteria: inability to wean steroids below 8 mg dexamethasone/day, Body Mass Index < 21 kg/m2, food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD or SD for a study period of 18 weeks, starting alongside chemoradiation. The primary outcome is overall survival for patients randomized to the KD arm compared to those randomized to the SD arm. Secondary outcomes include progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)). Patients randomized to the KD arm will be provided a fingerstick monitor to check blood ketone and glucose levels twice daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of May 2024, the trial is open for enrollment at Cedars-Sinai and UCSF, and will be opening soon at Duke, St. John’s Cancer Institute, and the Medical College of Wisconsin. 13 patients have been randomized to date. Funding provided by NIH R01CA276919 and the Foundation for Metabolic Cancer Therapies.
CTNI-68. UPDATES ON A POTENTIALLY PIVOTAL TRIAL CNS-201: A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM)
Authors: Silberman Sandra , Muzyczenko Zena
Published: November 2024

Berubicin, derived from doxorubicin (Dox), appears to cross the BBB and has shown significant central nervous system (CNS) uptake and anti-tumor activity. A current, potentially pivotal trial for patients with recurrent GBM after first-line therapy has completed enrollment in the US and Europe: a total of 252 patients were randomized 2:1 (Berubicin:Lomustine) after failure of prior therapy. All patients had to have certification of progression by a central reader, were Grade 4 IDH WT, and were stratified by MGMT methylation status. The primary endpoint, overall survival (OS), is maturing in this blinded trial; however, data will be presented that will document the demographics of the Berubicin and Lomustine arms, and provide a comparison of safety profiles and disposition of the patients enrolled on the study. Recently, a pre-planned non-binding futility analysis of the primary endpoint, OS, was evaluated when the trial reached ~30% of expected events (44 events). This interim analysis was performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB), which was additionally comprised of two oncologists. The DSMB’s charter mandated that they review the primary endpoint, OS, as well as secondary endpoints and safety data to determine whether these data for the risk-benefit profile warranted modification or discontinuation of the study. The DSMB recommended that the study continue as it was currently planned, with no modifications required, having met a pre-determined conditional endpoint. After the results of this interim analysis, CNS Pharmaceuticals completed enrollment with 252 patients evaluable for efficacy based on OS evaluations. Based on the decision of the DSMB, as well as the data presented herein, which includes comparative safety and balanced randomization of the arms, we will provide our recommendations and highlight our further development of Berubicin as a therapeutic option for patients with recurrent GBM as well as other CNS malignancies.
CTNI-70. RESULTS FROM THE PHASE 1 AND PHASE 1 EXPANSION COHORTS OF SJ901: A PHASE 1/2 TRIAL OF SINGLE-AGENT MIRDAMETINIB (PD-0325901) IN CHILDREN, ADOLESCENTS, AND YOUNG ADULTS WITH LOW-GRADE GLIOMA
Authors: Robinson Giles , Vinitsky Anna , Bag Asim , Chiang Jason , Li Qian , Lin Tong , Hoehn Mary Ellen , Edwards Angela , Storment Diana , Singh Anjali , Larkin Jennifer , Freeman Jana , Pranica Johanna , Bertrand Kelsey , Bagchi Aditi , Qaddoumi Ibrahim , Moreira Daniel , Baughman Todd , Hoang Thuy , Shearer Todd
Published: November 2024

BACKGROUND

Mirdametinib is an investigational, oral, selective MEK1/2 inhibitor (MEKi) with high blood-brain-barrier penetration. We hypothesized that mirdametinib would benefit patients with pediatric low-grade gliomas (pLGG) and launched SJ901 (NCT04923126) to determine the recommended Phase 2 dose (RP2D), safety, and efficacy.

METHODS

For Phase 1 and Phase 1 expansion patients were required to be ≥2 and <25 years-old, MEKi-naive, and have recurrent/progressive pLGG with biopsy-proven MAPK pathway activation (except BRAF V600). Three dose levels (DL1: 2 mg/m2/dose BID, DL2: 2.5mg/m2/dose BID, DL3: 3mg/m2/dose BID administered continuously in 28-day cycles) were evaluated with an expansion cohort to assess the highest tolerated dose level in a total of 12 patients. RP2D was defined as the dose causing ≤3 dose-limiting toxicities (DLTs) in 12 patients within the first cycle of therapy.

RESULTS

Between June 2021 and December 2023, 23 patients enrolled (DL1=5, DL2=6, and DL3=12). Median age was 8.4 years (2.5-21.9); 52% female. Alterations were seen in BRAF (n=12;52%), FGFR1 (n=5;22%), NF1 (n=3;13%), RAF1 (n=2;9%), and MYB (n=1;4%). The median follow-up time was 14.6 months (3.2-27.8). One DLT was observed (grade-3 thrombocytopenia). Seventeen (74%) patients completed or remain on-therapy; 4(17%) stopped for progression (2 FGFR1; 1 MYB; 1 BRAF); 2 discontinued for toxicities [1 grade-2 rash; 1 grade-4 creatine phosphokinase (CPK) elevation]. Dose modifying adverse events included weight gain, CPK elevations, and rash. No significant cardiac or retinal toxicity was observed. Twelve (63%) of 19 patients with measurable tumors achieved an objective response (1 major, 6 partial, 5 minor). The median time to ≥ minor response was 5.4 months (1.7-7.3). DL3 (3 mg/m2/dose BID) was declared the RP2D.

CONCLUSIONS

Mirdametinib is well-tolerated and has promising clinical activity in patients with recurrent/progressive pLGG. Phase 2 is ongoing to establish safety and efficacy in newly diagnosed, recurrent/refractory tumors, and in patients with prior MEKi exposure.