CTNI-41. INITIAL RESULTS OF A PHASE I WINDOW OF OPPORTUNITY TRIAL EVALUATING A FIRST-IN-CLASS CD29 INHIBITOR, OS2966, IN RECURRENT HIGH-GRADE GLIOMA

BACKGROUND OS2966 is a first-in-class, humanized, and deimmunized anti-CD29 (β1integrin) monoclonal antibody. CD29 is a mechanosignaling receptor prominently upregulated in glioblastoma. Preclinical studies in mice and non-human primates have demonstrated safety and encouraging efficacy. A phase I clinical trial was therefore initiated to evaluate the safety and feasibility of delivering OS2966 directly to the site of disease via convection-enhanced delivery (CED) in recurrent high-grade glioma patients. METHODS This study employs a 2-part design: In part 1, patients undergo stereotactic tumor biopsy followed by placement of a CED catheter(s) for delivery of OS2966 to the bulk contrast-enhancing tumor. Subsequently, in part 2, patients undergo a clinically-indicated tumor resection followed by placement of CED catheter(s) and delivery of OS2966 to the surrounding tumor-infiltrated brain. Co-convection of gadolinium enables real-time monitoring of therapeutic delivery. A concentration-based accelerated titration design is utilized for dose escalation. Given availability of pre and post-infusion samples, pharmacodynamic data will be analyzed to explore mechanism of action of OS2966. RESULTS Four patients have completed treatment in both study parts. No dose-limiting toxicity or adverse events related to treatment with OS2966 or CED catheter placement have been reported at the first 3 dose levels (ie, doses up to 0.6 mg/mL). For the four patients treated an average of 4.2 mL and 3.2 mL were infused in study parts 1 and 2 respectively. The Vd/Vi ratio ranged from 0.6 to 1.6 in part 1, and from 2.0 to 4.3 in Study Part 2. Analysis of tissue samples collected during the trial has demonstrated decreased VEGF expression post-treatment, with preinfusion samples showing > 50% VEGF expression and post-infusion samples showing 10% expression. Additional pharmacodynamic analysis via tissue-level biomarkers is ongoing and will be presented. CONCLUSION Initial data demonstrate the safety and feasibility of direct intracranial delivery of OS2966.

2069 Background: This Phase 0/1 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of recurrent high-grade glioma (HGG) patients with EGFR alterations and/or fusions to the ATP-competitive, irreversible EGFR inhibitor, BDTX-1535. Methods: Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 (200 mg) 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 enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug concentration above 5-fold biochemical IC50 in Gadolinium (Gd)-nonenhancing tumor, determined eligibility for Phase 1. 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. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of BDTX-1535. Results: A total of 7 patients with recurrent glioblastoma (Arm A) were enrolled in the Phase 0 component of the study. Two patients were excluded from PK analysis due to pseudoprogression. The mean unbound concentrations of BDTX-1535 in Gd-enhancing and nonenhancing tumor regions were 16.0 nM and 10.5 nM respectively. Four of five (80%) evaluable patients exceeded the PK threshold. The suppression of pEGFR and MIB1 was observed in 40% and 60% of patients, respectively. No serious adverse events were observed among patients in the Phase 1 component of the study and a clinical readout is planned in Q2 2024. Conclusions: BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue and is associated with suppression of EGFR signaling. Clinical trial information: NCT06072586 .

AAV Provides an Alternative for Gene Therapy of the Peripheral Sensory Nervous System

The presence of therapy-resistant cancer stem cells (CSCs) in recurrent high-grade glioma (HGG) patients contributes to poor clinical outcomes. The ChemoID functional anti-cancer assay targets cancer stem cells along with the bulk of the tumor cells. This trial aims to determine if ChemoID assay-guided treatment improves survival rates for recurrent HGG patients compared to the empirically physician-selected treatment. Patients with grade-III/IV recurrent glioma who failed standard of care (SOC) therapy were randomized (1:1) between two intervention groups. They received one of fourteen mono or combination chemotherapies based on the ChemoID assay or physician choice. The study met the primary outcome in the first interim analysis of 50 patients as per protocol. The ChemoID group had an improved survival rate (vs physician-choice). Median OS (mOS) was 12.5 months in the ChemoID group (95% CI, 10.2-14.7) vs 9 months in the physician-choice (95% CI, 4.2-13.8; log-rank P = .010). Mortality risk was lower in the ChemoID group (HR = 0.44; 95% CI, 0.24-0.81; P = .008). Median progression-free survival was 10.1 months in the ChemoID group vs 3.5 months in the physician choice (95% CI, 4.8-15.4 vs 1.9-5.1; log-rank < 0.001). Risk of progression was lower in the ChemoID group (HR = 0.25; 95% CI, 0.14-0.44; P < 0.001). The intention to treat (ITT) analysis of 78 patients showed substantially improved OS. The ChemoID group had a statistically significant longer median survival of 4.5 months. mOS was 12.0 months in the ChemoID group (95% CI, 10.8-13.2) vs 7.5 in the physician-choice group (95% CI, 3.5-11.5; log-rank P = .009). The ChemoID group had a decreased mortality risk (HR = 0.52; 95% CI, 0.24-0.81; P = .008). Compared with the physician-choice, the ChemoID group had a significantly longer OS in the ITT population. Our findings support that screening standard cytotoxic chemotherapies with a patient-specific anti-cancer assay improves survival outcomes in recurrent HGG patients.

<div>Abstract<p><b>Purpose:</b> Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).</p><p><b>Experimental Design:</b> Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 10<sup>7</sup> to 5 × 10<sup>7</sup> and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.</p><p><b>Results:</b> Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.</p><p><b>Conclusions:</b> Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. <i>Clin Cancer Res; 23(12); 2951–60. ©2016 AACR</i>.</p></div>

Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 107 to 5 × 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.Results: Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.Conclusions: Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. Clin Cancer Res; 23(12); 2951-60. ©2016 AACR.

<div>Abstract<p><b>Purpose:</b> Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).</p><p><b>Experimental Design:</b> Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 10<sup>7</sup> to 5 × 10<sup>7</sup> and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.</p><p><b>Results:</b> Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.</p><p><b>Conclusions:</b> Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. <i>Clin Cancer Res; 23(12); 2951–60. ©2016 AACR</i>.</p></div>

ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor, In Combination With Lenalidomide and Dexamethasone (dex), Is Well Tolerated Without Dose Limiting Toxicity (DLT) In Patients (Pts) With Multiple Myeloma (MM) At Doses Demonstrating Biologic Activity: Interim Results Of a Phase 1b Trial

2010 Background: Diffuse intrinsic pontine glioma (DIPG) represents one of the most deadly central nervous system tumors of childhood with a median survival of less than 12 months. Convection-enhanced delivery (CED) has been recently hypothesized as a means for augmenting distribution of therapeutic agents within the brain stem. We conducted this study to evaluate CED in children with DIPG. Methods: We performed a standard 3+3 phase I, open-label, dose escalation study in patients with non-progressive DIPG 4 to 14 weeks post-completion or radiation therapy. Seven dose levels of a single injection of 124I-8H9 (range 0.25 to 4.0 mCi, 250 to 4000 mcl) were studied. Results: 25 children were treated. The average age at enrollment 8 years old (range 3-17). There was no dose limiting toxicity (DLT) and adverse events were limited to grade 1 or 2 (CTCAE v4.0). Estimations of distribution volumes were dose dependent and ranged from 1.5 to 20.1 cm3. The mean volume of distribution/volume of infusion (Vd/Vi) was 3.4 (SD 1.2). The mean lesion absorbed dose was 1527 rad/mCi. The mean tumor coverage on dose level 7 was 107%. Conclusions: CED in the brain stem of children with DIPG who were previously irradiated is a safe therapeutic strategy. Up to 4 mCi of 124I-8H9 was well tolerated. An infusion volume of 4000 mcl appears to be a reasonable single dose for good tumor coverage. PET-based dosimetry validates the conceptual basis for direct drug delivery. Based on our finding CED merits further exploration in early phase clinical trials for children with DIPG. Clinical trial information: NCT01502917.

The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Striatal volume differences between non-human and human primates

Recurrent high grade glioma patients face a poor prognosis for which no curative treatment option currently exists. In contrast to prescribing high dose hypofractionated stereotactic radiotherapy (HFSRT, ge 6 Gy times 5 in daily fractions) with debulking intent, we suggest a personalized treatment strategy to improve tumor control by delivering high dose intermittent radiation treatment (iRT, ge 6 Gy times 1 every 6 weeks). We performed a simulation analysis to compare HFSRT, iRT and iRT plus boost (ge 6 Gy times 3 in daily fractions at time of progression) based on a mathematical model of tumor growth, radiation response and patient-specific evolution of resistance to additional treatments (pembrolizumab and bevacizumab). Model parameters were fitted from tumor growth curves of 16 patients enrolled in the phase 1 NCT02313272 trial that combined HFSRT with bevacizumab and pembrolizumab. Then, iRT +/− boost treatments were simulated and compared to HFSRT based on time to tumor regrowth. The modeling results demonstrated that iRT + boost(− boost) treatment was equal or superior to HFSRT in 15(11) out of 16 cases and that patients that remained responsive to pembrolizumab and bevacizumab would benefit most from iRT. Time to progression could be prolonged through the application of additional, intermittently delivered fractions. iRT hence provides a promising treatment option for recurrent high grade glioma patients for prospective clinical evaluation.

INTRODUCTION Blood–brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant glioma. Hypoxic tumor microenvironment impaired the effect of radiation induced cell death by Radiation therapy (RT). Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion in preclinical study. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). METHODS We aimed to report a 1-yr analysis of a single arm, prospective, pilot study (NCT04988750) of combining RT-FUS for recurrent high grade glioma patients, of whom re-RT was considered for disease focal control. In both preclinical and clinical studies, FUS-BBB opening protocol was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. RESULTS In the pilot clinical trial, enrolled 7 recurrent high grade glioma patients who underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. CONCLUSION Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the pilot clinical trial (NCT04988750) showed a combination of RT-FUS was safe (no FUS-related adverse effect) and a possible synergic effect.

153 Background: LAVA-1207 is a humanized bispecific antibody of 78 kDa comprised of two single domain antibody (VHH) fragments linked to a silenced fragment crystallizable immunoglobulin region. As shown pre-clinically, LAVA-1207 binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells, a potent immune effector cell population, and to prostate specific membrane antigen (PSMA) expressed by prostate cancer cells to trigger robust (pM range EC50) Vγ9Vδ2-T cell mediated lysis of prostate cancer cells, whereas normal cells are relatively spared. Based on earlier clinical experience with systemic activation of Vγ9Vδ2-T cells through aminobisphosphonates and in vivo studies in non-human primates with cross-reactive surrogate bispecific γδ-T cell engagers, a low risk for cytokine release syndrome (CRS) is expected in the clinic. Methods: This is an open label, 3+3 design, phase 1/2a study in patients with therapy refractory metastatic castration resistant prostate cancer (NCT05369000; EudraCT Number: 2021-001789-39) to determine the safety of LAVA-1207 and its recommended Phase 2a dose (RP2D) and schedule. Secondary objectives include evaluation of PK, PD, immunogenicity, and preliminary antitumor activity. LAVA-1207 is administered IV every two weeks with an infusion duration of 2 hours for the first dose, 1 hour for the second dose, and 30 minutes for all subsequent doses. Results: As of September 23, 2022, a dose level of 40 µg (starting dose was 1.5 µg based on MABEL approach) has been reached without dose limiting toxicities (DLTs). A total of 16 patients have been treated with LAVA-1207 with treatment duration ranging from 1 to 25+ weeks. Treatment emergent AEs (TEAEs) that were suspected to be related were all grade 1-2, and included nausea (n=3), AST increase (n=2), fatigue (n=2), and infusion related reaction (n=2). Severity of TEAEs did not increase with escalating doses and no patient discontinued treatment due to an AE. PK data indicate increasing drug exposure in correlation with increasing doses of LAVA-1207. PD data show a consistent early reduction in Vγ9Vδ2-T cell frequencies at 2hrs after the first dose, which could be indicative of Vγ9Vδ2-T cell redistribution after treatment, often accompanied by an increase in Vγ9Vδ2-T cell activation markers. Vγ9Vδ2-T cell numbers are restored in the subsequent 3 to 5 days to at least pre-dose levels. Additionally, receptor occupancy of Vγ9Vδ2-T cells was detectable up to 5 days after first dosing. To date, stable disease at 8 weeks has been observed in 3 out of 8 evaluable patients. Conclusions: LAVA-1207 has been well tolerated early in dose escalation; further clinical activity including PSA results, response assessment, and pharmacodynamic data will clarify determination of an optimal biological active dose. Clinical trial information: NCT05369000 .

BACKGROUND This study(NCT 03904628) is a dose-escalation, open-label phase I study which enrolled high grade glioma patients who failed with temozolomide(TMZ) treatment. The study purpose is to investigate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of an multi-kinase inhibitor (TG02 capsule, with primary inhibitory effects on cyclin-dependent kinases), as a new therapy for patients with recurrent high-grade glioma patients. METHODS The key inclusion criteria were 18-75 years old, glioblastoma or anaplastic astrocytoma confirmed by histology; when disease progression after receiving temozolomide; according to RANO criteria had evaluable lesions; ECOG performance status of 0-2. Eligible patients were enrolled sequentially into different dose groups and received TG02 capsule every 4 weeks .The dose was increased in a traditional 3 + 3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose(MTD). Second endpoints were pharmacokinetic characteristics and preliminary efficacy. RESULTS Between May 2019 and November 2021, twelve patients were enrolled. No DLT was occurred and MTD was not defined in study. The plasma concentration of TG02 reached the maximum at 2 h after administration, and the elimination half-life was about 7 h. Eleven patients(91.7%) had one or more treatment-related adverse events (TRAEs) assessed using CTCAE 5.0. Most frequent TRAEs were vomiting (91.7%), diarrhea (75.0%), and 50% of the patients had grade 3 or 4 AEs. There were no treatment-related deaths. The median progression-free survival (PFS) was 1.77 months (95%CI:0.82 ~ 4.24). The median OS was 9.63 months (95%CI:2.66 ~ NE). CONCLUSION TG02 capsule is safe and tolerable in patients with recurrent high-grade gliomas. Switching to using TG02 capsule showed some patients had intracranial tumor reduction who failed to treat with TMZ. TG02 can be further explored with combined therapy in the treatment of gliomas.