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This study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy. Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. All patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. In Arms A (n = 20) and B (n = 15), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 102.9 nM, respectively and in Arm C (n = 4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively progressed to expansion phase. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.4 (Arm A) (n = 7), 5.0 months (Arm B) (n = 6), and 2.7 months (Arm C) (n = 1), respectively. Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.

BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients to a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. METHODS Presumed newly-diagnosed GBM patients received 4 days of niraparib (300 mg QD) prior to planned resection at 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. Patients with unmethylated MGMT tumors exceeding the PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. RESULTS Nineteen patients were enrolled into the Phase 0 study; all tumors met the study’s PK threshold and five unmethylated patients continued onto the expansion phase. One expansion phase patient experienced treatment-related Grade 3 serious adverse event (ALT and AST elevation) and four remain on treatment (median 4.2 months). In nonenhancing regions, the mean unbound concentrations of niraparib were 353.4 nM and 331.9 nM in the 3-5 hr cohort (n= 17) and the 8-12 hr (n = 3) cohort, respectively. The suppression of PAR levels after ex vivo radiation was observed in 69% of the patients (11/16). CONCLUSIONS Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.

BACKGROUND For patients with operable intracranial neoplasms, there are opportunities to augment local control beyond traditional methods, such as external beam radiation therapy. Brachytherapy, the implantation of radioactive sources into the resection cavity, can be useful in this setting by providing immediate initiation of radiation and limiting the exposure of surrounding normal tissue to radiation. Traditional intracranial brachytherapy has been limited by uneven dose distributions, complicated workflows, extended procedural times, cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT), it is FDA-cleared for use in newly-diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, and has demonstrated excellent safety and efficacy in early commercial use. The primary objectives of this multicenter, prospective, observational (phase IV) registry study are to evaluate “real-world” clinical outcomes and patient-reported outcomes that measure the safety and efficacy of STaRT using the GammaTile. METHODS Patients undergoing resection (R) of brain tumors with intra-operative GammaTile placement are eligible for enrollment. Planned sample size is 600 at up to 50 enrolling sites. First subject was enrolled 10/14/2020. Tumor pathology, overall survival, radiation- and surgery-related adverse events, patient- and provider-reported quality of life, serial MRIs, and timing of surgical bed and/or distant recurrence are collected. Powered primary endpoints for recurrent brain metastases, recurrent glioblastoma, and recurrent meningioma (surgical bed-progression free survival (PFS), overall survival, and PFS, respectively), compare STaRT to standard-of-care benchmarks. Results will be used to improve awareness and access to this treatment, benchmark clinical outcomes in the real-world setting, allow for comparisons to existing treatments, facilitate the design of future clinical trials, and contribute to the optimal sequencing of treatments for intracranial neoplasms.

Background For patients with operable intracranial neoplasms, there are opportunities to augment local control beyond traditional methods, such as external beam radiation therapy (EBRT),. Brachytherapy, the implantation of radioactive sources into the resection cavity, can be useful in this setting by providing immediate initiation of radiation and limiting the exposure of surrounding normal tissue to radiation. Traditional intracranial brachytherapy methods have been limited by uneven dose distributions, complicated workflows, extended procedural times, the cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT), it is FDA-cleared for use in newly-diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, including brain metastases, and has demonstrated excellent safety and local control in early commercial use. The primary objectives of this multicenter, prospective, observational (phase IV) registry study [NCT04427384] are to evaluate “real-world” clinical outcomes and patient-reported outcomes that measure the safety and efficacy of STaRT using the device. Methods Subjects (N=600) at up to 50 enrolling sites undergoing resection of brain tumors of any pathology with intra-operative GammaTile placement are eligible for enrollment. We project 40% of enrollees to have brain metastasis. Tumor pathology, overall survival, radiation- and surgery-related adverse events, quality of life, serial MRIs, and timing of surgical bed recurrence and/or distant recurrence will be collected. The powered primary endpoint for recurrent brain metastases, surgical bed-progression free survival, will compare STaRT to standard-of-care benchmarks. This study will be the first observational study of resection plus GammaTile. Results will be used to benchmark clinical outcomes in the real-world setting, allow for comparisons to existing treatments, and facilitate the design of future clinical trials.

Failure of skin flaps remains a significant clinical problem. The dorsal rat flap, a reliable experimental model, was used to test the efficacy of cimetidine in treating a failing flap. Flaps were elevated in 45 rats divided into three equal groups. Group 1 was a saline control group, Group 2 received cimetidine 250 mg/kg three times a day for 7 days postoperatively, and Group 3 received cimetidine for 1 day before surgery, and then as in Group 2. Necrosis was assessed on the seventh postoperative day. Group 2 had 31.1 +/- 1.3 (mean % +/- SEM) necrosis, significantly better than saline control animals (p less than 0.01) and pretreated animals (p less than 0.05). These results suggest the usefulness of cimetidine in ischemic flap surgery.