Phase Ib study of olinvacimab (O) with pembrolizumab (P) in patients with recurrent glioblastoma (rGBM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14545-e14545
Author(s):  
Anna K. Nowak ◽  
Lawrence Cher ◽  
Samantha Bowyer ◽  
Hui Kong Gan ◽  
Anne Poh Long ◽  
...  
Keyword(s):  
Dose Level ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Blurred Vision ◽  
Flat Dose ◽  
Best Response ◽  
Grade 3

e14545 Background: Recurrent GBM is difficult to treat. Single agent checkpoint blockade has not improved outcomes. Angiogenesis is a rational drug target for rGBM and targeting angiogenesis may benefit pseudoprogression and cerebral oedema. O is a fully human monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) with antiangiogenic and antitumour effects. P is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O combined with P and to establish a recommended phase 2 combination dose. Methods: From January to October 2019, we conducted a two-site, single arm, open-label study of O with P in patients with rGBM. Eligible patients (pts) were ≥18 years with at least one RANO-measurable lesion, KPS≥80, and had completed standard chemoradiotherapy and had no contraindications to O or P. No prior bevacizumab was allowed. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg day 1/8/15 q21d (dose level 1) or O 16mg/kg day 1/8/15 q21d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Pts were reviewed weekly and underwent DCE-MRI at baseline and 6-weekly. Treatment continued to progression, toxicity or withdrawal. Results: 9 pts, median age 53 (range 34-67) were recruited and received at least one study treatment. Median time since diagnosis was 15.6 months. 7 (78%) had KPS 90 and 2 (22%) KPS 80. 3 pts received O 12mg/kg with P, completing a median 3 cycles (range 2-6). As no Dose Limiting Toxicities (DLTs) were seen, 3 pts were treated with O 16mg/kg with expansion total 6 when no DLTs were observed. At 16mg/kg, a median of 2 treatment cycles was received (range 2-6). Treatment was ceased due to progressive disease (PD) in 8 pts with one ongoing at data cutoff. No DLTs were observed in any pts. Three grade 3 treatment emergent adverse events (TEAEs) were noted (blurred vision, fatigue, and seizure). Hemangioma is a known toxicity of O and was seen in 6 pts, with 11 grade 1 and 1 grade 2 event. 4 pts (44%) had stable disease (SD) and 5 pts (56%) had PD as best response. Conclusions: The combination of O with P was safe and tolerable at the full single agent dose of each drug. No DLTs were observed. The combination did not show efficacy in this setting. Clinical trial information: NCT03722342.

Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 318-318 ◽  
Author(s):  
T. Doi ◽  
N. Fuse ◽  
T. Yoshino ◽  
H. Murakami ◽  
N. Yamamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Best Response ◽  
Grade 3

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]

Phase Ib trial of combining aldoxorubicin plus doxorubicin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2550-2550
Author(s):  
Kamalesh Kumar Sankhala ◽  
Sant P. Chawla ◽  
Victoria S Chua ◽  
Doris Quon ◽  
Allison Bonk ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Safety Data ◽  
Tumor Xenograft ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3

2550 Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv + 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 mg/m2 aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) + doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.

Vorinostat Plus Bortezomib for the Treatment of Relapsed/Refractory Multiple Myeloma: Early Clinical Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 871-871 ◽  
Author(s):  
Donna Weber ◽  
Ashraf Z. Badros ◽  
Sundar Jagannath ◽  
David Siegel ◽  
Victoria Richon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Level ◽  
Progressive Disease ◽  
Maximum Tolerated Dose ◽  
Phase I Clinical Trials ◽  
Open Label ◽  
Best Response ◽  
Open Label Phase ◽  
Grade 3

Abstract Bortezomib, a proteasome inhibitor, is extremely effective for the treatment of multiple myeloma (MM). However, nearly all patients will eventually become refractory to bortezomib. Vorinostat is a potent inhibitor of histone deacetylase enzymes, and has been shown to affect growth of various cell lines, including MM, in a variety of in vitro non-clinical studies. Furthermore, the combination of bortezomib and vorinostat has demonstrated synergy in several in vitro and murine models. Subsequently, 2 multicenter, open-label, Phase I clinical trials have been conducted to investigate the combination of vorinostat with bortezomib in patients with MM. In the first trial, 34 patients with relapsed/refractory MM were enrolled. Patients received escalating doses of vorinostat (200 mg bid or 300–400 mg daily for 14 days) and bortezomib (0.7, 0.9, 1.1, or 1.3 mg/m2 on days 1, 4, 8, and 11); cycles were repeated every 21 days for ≤8 cycles or until progressive disease (PD) or intolerable toxicity. In the event of PD, oral dexamethasone (20 mg on days 1–4 and 17–20) could be added to the bortezomib plus vorinostat combination. The highest dose level of vorinostat was 400 mg daily for 14 days and bortezomib 1.3 mg/m2. The maximum tolerated dose (MTD) was not determined because ≥2 dose-limiting toxicities (DLTs) did not occur at any dose level. The most common drug-related adverse events were nausea (61.8%), diarrhea (58.8%), thrombocytopenia (50%), and vomiting (50%). Two patients experienced a DLT; grade 3 transient AST elevation was experienced by 1 patient receiving 400 mg vorinostat daily and 0.9 mg/m2 bortezomib, and grade 4 thrombocytopenia was experienced by 1 patient receiving 400 mg vorinostat daily and 1.3 mg/m2 bortezomib. Among 34 evaluable patients, the best response to vorinostat plus bortezomib was a partial response (PR) in 9 (26%) patients, minimal response (MR) in 7 (21%) patients, and stable disease (SD) in 18 (53%) patients. Mean duration of SD was 89 days, range 9–369 days. Of the 13 evaluable patients who had previously been treated with bortezomib, 5 achieved a PR, 1 had a MR, and 7 had SD. The effect of adding dexamethasone will also be analyzed and presented. The second trial enrolled 23 patients who received vorinostat (100–500 mg on days 4–11) and bortezomib (1–1.3 mg/m2 on days 1, 4, 8, and 11). Dexamethasone was added at cycle 2 for 6 patients who achieved less than a PR, and at cycle 4 for 5 patients with PD and at cycle 6 for 2 patients with PD. There was no upgrade in response for any patients who received additional dexamethasone. Two patients in the vorinostat 500 mg group experienced DLT (fatigue and prolonged QTc); MTD was identified as vorinostat 400 mg plus bortezomib 1.3 mg/m2. The main toxicities in this trial were hematologic (anemia, neutropenia, and thrombocytopenia). Twenty-one patients were evaluable for response (2 achieved very good PR, 7 PR, 10 SD, 2 progressive PD). Of the 9 patients who were refractory to bortezomib, 3 had PR, 4 had SD, 1 had PD, and 1 was non-evaluable. Co-administration of bortezomib did not alter the pharmacokinetics of vorinostat. In conclusion, these data suggest that the combination of vorinostat plus bortezomib is active for treatment of MM, even among some patients with prior exposure to bortezomib.

scholarly journals CTNI-47. PHASE II STUDY OF ABEMACICLIB IN RECURRENT GBM PATIENTS WITH CDKN2A/B LOSS AND INTACT RB

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii53-ii53
Author(s):  
Eudocia Lee ◽  
Alona Muzikansky ◽  
Isabel Arrillaga-Romany ◽  
Ugonma Chukwueke ◽  
Timothy Cloughesy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Recurrent Glioblastoma ◽  
Open Label ◽  
Cyclin Dependent Kinases ◽  
Best Response ◽  
Common Grade ◽  
First Relapse ◽  
Grade 3 ◽  
Recurrent Gbm

Abstract Deregulation of the cyclin-dependent kinases (CDK) 4 and 6 (cdk4/6)–cyclin D-INK4—retinoblastoma protein (Rb) signaling pathway is among the most common aberrations found in glioblastoma (GBM) with more than 80% of patients estimated to be affected. We conducted an open label, multi-center, phase II trial of abemaciclib in participants with recurrent glioblastoma (GBM) at their first relapse and with documented evidence of CDKN2A/B loss and intact RB from archival tissue. A total of 32 patients enrolled on the non-surgical arm of the study with 13 women (40.63%) and median KPS 90 [range 60–100]. The PFS6 rate was 9.37% [95% CI, 2.4%, 22.27%], median PFS 55 days [95% CI, 49, 56], and median OS 384 days [95% CI, 228, 488]. Out of 31 evaluable patients, best response was PR 1 (3.2%), SD 11 (35.5%), and PD 19 (61.3%). The most common grade 3 or higher toxicities at least possibly related to abemaciclib included leukopenia (21.9%), neutropenia (18.6%), lymphopenia (9.4%), and thrombocytopenia (6.3%). Abemaciclib has minimal activity in this preselected recurrent GBM population. Correlative studies from the surgical arm of this study are pending.

A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2609-2609 ◽  
Author(s):  
Monica Arnedos ◽  
Crystal Shereen Denlinger ◽  
Wael A. Harb ◽  
Olivier Rixe ◽  
John Charles Morris ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Clinical Benefit Rate

2609 Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n=11), carboplatin (Arm B, n=11), pemetrexed (Arm C, n=10), or cabazitaxel (Arm D, n=11). Methods: Patients were treated in a dose escalation “3+3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (>20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD >18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

GLIAVAX: A stratified phase II clinical trial of avelumab and axitinib in patients with recurrent glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2034-2034 ◽  
Author(s):  
Bart Neyns ◽  
Laila Ben Salama ◽  
Gil Awada ◽  
Jennifer De Cremer ◽  
Julia Katharina Schwarze ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Clinical Activity ◽  
Open Label ◽  
Grade 5 ◽  
Phase 2 Clinical Trial ◽  
Prior Surgery ◽  
Grade 3 ◽  
Tumor Types

2034 Background: Patients (pts) with recurrent glioblastoma (rGB) have a poor prognosis, and no treatment option demonstrated to improve survival in a randomized trial. Axitinib (AXI), an oral VEGFR 1-3 inhibitor has demonstrated single agent activity in rGB and reduces the need for corticosteroids (CS). Avelumab (AVE) is a fully human anti-PD-L1 IgG1 antibody with clinical activity in various tumor types. Combination of AXI and AVE may improve the outcome of pts with rGB. Methods: This open-label, dual-strata, single-center phase 2 clinical trial investigated the activity of AXI plus AVE in adult pts with rGB following prior surgery, RT and temozolomide. Pts were stratified according to their baseline use of CS. Pts without baseline need for CS initiated treatment with AXI (5 mg oral BID) plus AVE (10 mg/kg IV Q2W) (cohort-1). Pts in need of CS initiated AXI as a monotherapy; AVE could be added to AXI after 6 wks if the CS dose could be tapered to a physiologic dose level or less (cohort-2). Six-month-PFS served as the primary endpoint (with a prespecified threshold of ≥ 50% for cohort-1) according to Fleming one-stage design. Results: Between Jun 2017 and Aug 2018, 54 pts (27 per cohort) were enrolled (med age 55 y [range 19-75]; 63% male; 91% WHO PS 0-1). All pts in cohort-1 and 16 pts (59%) in cohort-2 received at least 1 dose of AVE. The 6-month-PFS was 18% (95% CI 4-33) in both cohorts. At the time of analysis, 2 pts were progression-free and continuing study treatment. Median OS in cohort-1 and -2 was respectively 26 wks (95% CI 21-32) and 18 wks (95% CI 14-22). No clear relation was found between baseline cognitive functioning (Cogstate subtests) and PFS/OS. The best overall response rate (iRANO) was 41% and 26% respectively for pts in cohort-1 and -2. The most frequent all-grade treatment-related adverse events (TRAE) were dysphonia (67%), lymphopenia (50%), diarrhea (48%), hypertension (48%), and fatigue (46%). The incidence of grade 3-4 TRAE was 30%; there were no grade 5 AE. Conclusions: The combination of AVE plus AXI is sufficiently well tolerated but did not meet the threshold for activity justifying further investigation in an unselected population of patients with rGB. Clinical trial information: NCT03291314.

Tremelimumab in combination with exemestane as novel immunotherapy for patients with advanced breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3034-3034
Author(s):  
R. H. Vonderheide ◽  
P. M. LoRusso ◽  
M. Khalil ◽  
E. Heath ◽  
D. Khaira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Hormone Replacement ◽  
Single Agent ◽  
Pharmacokinetic Interaction ◽  
Open Label ◽  
Receptor Status ◽  
Best Response ◽  
Grade 3 ◽  
Factor Α

3034 Background: Tremelimumab (CP-675, 206) is a fully human IgG2 anti-CTLA4 monoclonal antibody (mAb) with single-agent antitumor activity presumed to be related to immune stimulation following blockade of CTLA4. Here, we conducted a phase I, open-label, dose-escalation trial of the combination of tremelimumab and exemestane in patients (pts) with advanced hormone receptor (or unknown receptor status if prior response with hormone therapy) breast cancer. Methods: Twenty-five pts with ER+ and/or PR+ breast cancer and 1 pt with unknown receptor status who had relapsed after treatment for advanced disease were enrolled. Pts received escalating doses of tremelimumab (3 to 10 mg/kg) delivered either every 28 days (Q28D) or every 90 days (Q90D) in combination with continuous exemestane (25 mg/day). Primary endpoints were assessment of safety and determination of recommended phase II dose. Tumor response evaluation per RECIST was a secondary endpoint. Results: Overall, 65 cycles of tremelimumab were administered in combination with exemestane. Pts received 3 mg/kg tremelimumab Q28D (n=6), 6 mg/kg tremelimumab Q28D (n=1), 6 mg/kg tremelimumab Q90D (n=13), or 10 mg/kg Q90D (n=6). No pharmacokinetic interaction between tremelimumab and exemestane was observed. Dose-limiting toxicities included transient serum transaminase elevation in cycle 1 (grade 3 in 1 pt) and diarrhea in cycle 1 (grade 3 in 3 pts, 1 of whom was hospitalized with steroid-refractory diarrhea and given anti-tumor necrosis factor-α mAb, infliximab) and cycle 2 (grade 3 in 1 pt). One pt developed grade 2 autoimmune thyroiditis requiring chronic hormone replacement. Other toxicities included constipation (n=6), fatigue (n=8), and rash (n=9). The MTD was 6 mg/kg Q90D. For pts receiving ≥2 cycles of therapy, best response was stable disease in 8 pts lasting 3 to 14 months (median 8 months); no pts had objective responses. Conclusions: MTD of tremelimumab in combination with exemestane is estimated at 6 mg/kg Q90D, which is lower than the single-agent dose of 15 mg/kg Q90D used in phase II and III trials in pts with melanoma or colorectal cancer. This may suggest that there is a biological interaction between tremelimumab and exemestane. [Table: see text]

A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients (pts) with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5502-5502 ◽  
Author(s):  
Jordi Giralt ◽  
Andre Fortin ◽  
Ricard Mesia ◽  
Heikki Minn ◽  
Michael Henke ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Mucosal Inflammation ◽  
Open Label ◽  
Hpv Status ◽  
Biomarker Analysis ◽  
Grade 3 ◽  
Fatal Adverse Events ◽  
Ecog Ps

5502 Background: Pmab is a fully human monoclonal antibody against the epidermal growth factor receptor. We evaluated the safety and efficacy in pts receiving CRT alone or CRT plus pmab (PCRT) as 1st‑line treatment of LASCCHN (sponsored and funded by Amgen Inc.). Methods: Pts with stage III, IVA, or IVB previously untreated LASCCHN of all sites excluding the nasopharynx were randomized 2:3 to open-label CRT or PCRT. CRT included cisplatin 100 mg/m2 for 3 cycles during standard fractionation radiotherapy (RT). PCRT included pmab 9.0 mg/kg + cisplatin 75 mg/m2, both administered with RT as in the CRT arm. The primary endpoint was local regional control (LRC) rate at 2 years; key secondary endpoints included PFS, OS, and safety. Preplanned HPV subset analysis, as determined by p16 immunohistochemistry, was performed on available samples. Results: Of 150 treated pts (87 pts PCRT, 63 pts CRT), 87% were men; median (range) age was 57 (39-77) years; ECOG PS 0: 68%. Of 99 pts with tumor evaluable for HPV, 42% were HPV+. Overall, the 2-year LRC rate (95% CI) was 61% (50%-71%) for PCRT and 68% (54%-78%) for CRT. PFS events occurred in 40% of the PCRT and 35% of CRT arm (HR [95% CI] 1.15 [0.68-1.96]; p=0.61). Death occurred in 36% of the PCRT arm vs 24% of the CRT arm (HR [95% Cl] for OS 1.63 [0.88-3.02]; p=0.12). Disease progression was the cause of death in 22% of PCRT pts and 10% of CRT pts. There were no differences in outcome by tumor HPV status. No difference in fatal adverse events (AEs) was seen between arms. Grade 3+ AEs occurred in 85% vs 68% of pts (PCRT vs CRT). Differences in grade 3+ toxicity between treatment arms (PCRT, CRT) were most pronounced for mucosal inflammation (55%, 24%), radiation skin injury (28%, 13%), dysphagia (40%, 27%), and rash (11%, 0%). RT delays of >10 days occurred in 16% of the PCRT arm and 3% of the CRT arm. Median cisplatin cumulative dose received was 223.1 mg/m2 in the PCRT arm and 296.9 mg/m2 in the CRT arm, reflective of differences in planned dose. Conclusions: The addition of pmab to CRT did not show an increase in efficacy and was associated with increased toxicity. Further results of HPV biomarker analysis will be presented.

Pharmacodynamic and safety study of reolysin in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14004-14004 ◽  
Author(s):  
R. Gollamudi ◽  
K. Desai ◽  
I. Chaudhary ◽  
M. H. Ghalib ◽  
B. Wong ◽  
...  
Keyword(s):  
Performance Status ◽  
Single Agent ◽  
Neutralizing Antibody ◽  
Open Label ◽  
Viral Shedding ◽  
Cytopathic Effects ◽  
Best Response ◽  
Activating Mutation ◽  
Grade 3 ◽  
Anti Tumor Activity

14004 Background: Reolysin is an intravenous formulation of reovirus serotype 3 - Dearing strain which is a double stranded RNA non-enveloped icosahedral virus capable of inducing cytopathic effects in cancer cells that have an activating mutation in the ras protooncogene. Pre clinical testing has identified cancer cell lines as being susceptible to reovirus infection. Methods: This was an open- label single center phase I safety and dose escalation trial of reolysin administered intravenously over 1 hour on day 0 in a 28 day cycle. Dose escalations were in half log increments. Serum for neutralizing antibody (NA) was drawn at baseline, and days (d) 1, 7, 14, 21, and 28, and serum, stool, saliva, and urine for viral shedding (by RT-PCR) were sampled on d 1,7,14,21, and 28. Response was assessed by imaging studies after 1, 3, 5, and 7 cycles. Results: 18 patients (pt); median age 57 (40–72) years; performance status 0–1; diagnoses - ovarian (6), colorectal (5), and others (7) received 27 cycles of reolysin (median 1, range 1–7) in 6 dose cohorts of 1x108, 3x108, 1x109, 3x109, 1x1010, and 3x1010 tissue culture infective dose (TCID)50. No protocol defined dose limiting toxicities were observed. Drug related grade 2 toxicities included chills (2 pt), and fatigue (3 pt). The only grade 3 event was fever in cycle 7 in a 57 year old woman with progressive breast cancer, treated at a dose of 1x1010 TCID50. She was noted to have 28.5% shrinkage in objective tumor volume. An additional 7 pt had stable disease (SD). No NA was detectable in the serum in any pt at baseline; however all pt developed NA (on d 5 in 5 pt, d 8 in 11 pt, d 14 in 1 pt, and d 28 in 1 pt) during the course of the study. Viral shedding was observed in serum - 5 pt, stool - 3 pt, saliva - 3 pt, and urine - 4 pt. Of interest, 4 of 5 pt with viral shedding had SD as their best response. However, there was no observed relationship between NA formation and SD. Conclusion: Reolysin administered as a one hour infusion on a monthly schedule is safe and well-tolerated even in multiple doses. This preliminary data suggests there is anti-tumor activity of reolysin as a single agent, and warrants further studies either alone or in combination with cytotoxic chemotherapy. [Table: see text]

scholarly journals EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
Christine Fuller ◽  
Olivia Campagne ◽  
Tong Lin ◽  
Haitao Pan ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Single Agent ◽  
Pediatric Brain Tumor ◽  
Pi3k Pathway ◽  
Neurosurgical Procedures ◽  
Common Grade ◽  
Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

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