scholarly journals Safety and Pharmacokinetics Of Clofarabine In Combination With High-Dose Cytarabine and Liposomal Daunorubicin In Pediatric AML: Results Of a Phase 1 Combination Study By The ITCC Consortium

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2693-2693 ◽  
Author(s):  
Christian M. Zwaan ◽  
Michael Dworzak ◽  
Thomas Klingebiel ◽  
Claudia Rossig ◽  
Guy Leverger ◽  
...  
Keyword(s):  
Dose Level ◽  
Dose Escalation ◽  
Fungal Infections ◽  
Single Agent ◽  
Lung Infection ◽  
High Dose ◽  
Liposomal Daunorubicin ◽  
Candida Sepsis ◽  
Pediatric Aml ◽  
Dose Levels

Abstract Introduction Relapsed/refractory pediatric AML has a poor prognosis despite salvage therapy including stem-cell transplantation. Chemotherapy using FLAG plus liposomal daunorubicine (FLAG-DNX) is currently considered the standard in 1strelapse in Europe (Kaspers et al, JCO 2013). FLAG is based on potentiation of cytarabine (Ara-C) by fludarabine (Flu) by increasing Ara-CTP levels. Clofarabine (CLO) is a novel purine nucleoside analog, designed to have improved efficacy. Methods We initiated an ongoing phase 1B dose-escalation study using a ‘3x3 design’ to define the optimal dose of CLO, replacing FLU in FLAG-DNX. Dosages consisted of Ara-C 2gr/m2/day (day 1-5), with escalation of DNX from 40, 60 to 80 mg/m2/day (day 1, 3 and 5), and CLO from 20, 30 to 40 mg/m2/day (day 1-5) in 5 dose-levels, without GCSF priming. At day 6 intrathecal Ara-C was administered. Dose-level 1-4 recruited early 1st relapse, refractory 1st relapse and 2nd relapse of AML, and escalated CLO to 40 mg/m2 with DNX 60 mg/m2. Dose level 5 is open to 1st relapse pts and escalates DNX to 80 mg/m2. Responding patients received a 2ndconsolidation with CLARA-DNX or treated by investigator discretion. Other inclusion criteria consisted of performance status ≥60%, and normal liver and renal function. Maximum tolerated dose was the primary endpoint. Hematologic DLTs were defined as count recovery in responding pts >42 days. Serum and CSF were collected for pharmacokinetics (PK), taken at day 1: predose, T=2hrs and T=5 hrs post-infusion, and repeated on day 5, including a T=24 sample on day 6, together with a CSF sample just prior to intrathecal medication. CLO plasma and CSF concentrations were analyzed using LC-MS/MS. Efficacy data are awaiting central review and not released until the end of the study. The study is registered in the Dutch Trial Registry (nr. 1880). Results We here report safety and PK data on the first 4 dose-levels after accrual of 22 AML patients (≥2nd relapse, n=7; refractory 1st relapse, n=9; early 1strelapse, n=6). Patients were treated at dose-level (DL) 1, n=4; 2, n=3; 3, n=12; 4, n=3. Eleven patients had been transplanted prior to enrollment. In total 27 CLARA-DNX courses were administered. Median age was 6.4 years, 14 patients were male. 20 SAEs were reported, consisting of febrile neutropenia (n=11), typhlitis (n=1), lung-infection fungal (n=3), lung-infection bacterial (n=2), candida sepsis (n=1), rash (hand-foot skin reaction) (n=1), and tumor lysis/capillary leak syndrome (n=1). Other grade 3-4 AEs reported in at least 2 patients consisted of abdominal pain, nausea and vomiting, diarrhea, anorexia and allergic reaction. Two patients had bilirubin elevation (max 61 umol/l); six patients had mild transaminase elevation > 100 U/l (max. 330U/l), which was reversible. At dose-level 3, two patients experienced DLTs (fungal infection) halting dose-escalation. Detailed analysis showed that most patients had evidence of subclinical fungal infections prior to enrollment. Therefore a protocol amendment was issued that required screening patients with CT-scan and serum-galactomannan prior to enrollment. After enrolling another cohort of 6 patients at DL3 this appeared to be safe (1 DLT of Candida sepsis out of 6 patients). No DLTs occurred at dose-level 4 in 3 patients. No hematological DLTs occurred. PK samples were available from 19 patients; in 2 patients sampling was repeated at course 2. At day 1 the median AUC was 28 ng/ml.mg.hr (range 6-401), with a mean T1/2 of 1.5 hrs. Day 1 and day 5 results were similar. CSF levels were not measurable in most patients and were 0.1-0.2 ng/ml.mg in the 3 patients with detectable levels. Our PK-data in combination are not significantly different from our data with single-agent CLO in relapsed ALL patients (Joel et al, AACR, 2007), and fit the CLO single agent PK model of Bonate et al (J Clin Pharmacol 2004, 44: 1309-32) . Conclusions The RP2D of CLO in a CLARA/DNX course in relapsed/refractory pediatric AML is 40 mg/m2, excluding patients with evidence of prior subclinical aspergillus. There is no evidence for PK interaction between CLO and the other drugs. We are currently testing the safety of an augmented dose of DNX (80 mg/m2) in 1strelapse AML patients. When tolerable this dose may be randomized against other induction regimens in front-line therapy in pediatric AML. Acknowledgment This study was financially supported by Sanofi and by the KiKa-foundation grant nr. 26. Disclosures: Off Label Use: Clofarabine for pediatric AML.

Lenalidomide, Bortezomib, and Dexamethasone (Rev/Vel/Dex) as Front-Line Therapy for Patients with Multiple Myeloma (MM): Preliminary Results of a Phase 1/2 Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 187-187 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Noopur Raje ◽  
Andrzej Jakubowiak ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Front Line ◽  
Dose Levels ◽  
Dose Reductions

Abstract Background: Bortezomib (VELCADE®, Vel) as a single agent and lenalidomide (Revlimid®, Rev) plus dexamethasone (Dex) are approved for the treatment of relapsed MM patients (pts) following ≥1 prior therapy. Rev/Vel±Dex is active and well tolerated in relapsed/refractory MM, and Rev/Dex and Vel/Dex have substantial activity in front-line MM. The aims of this phase 1/2 study were to determine the MTD of Rev/Vel/Dex in newly diagnosed MM pts, and to assess safety and efficacy. Methods: Pts received Rev 15–25 mg on d 1–14, Vel 1.0–1.3 mg/m2 on d 1, 4, 8, 11, and Dex 40/20 mg (cycles 1–4/5–8) on d 1, 2, 4, 5, 8, 9, 11, 12, for up to 8 21-d cycles, initially at 4 planned dose levels (Rev/Vel: 15/1.0, 15/1.3, 20/1.3, 25/1.3). Dose escalation proceeded (3-pt cohorts) depending on DLTs (G≥3 non-hematologic toxicity; G4 thrombocytopenia with platelets <10,000/mm3 on >1 occasion despite transfusion support; G4 neutropenia for >5 d and/or resulting in neutropenic fever; inability to receive cycle 2/d 1 dose due to drug-related toxicity). Based on safety data, dose level 4M was added with a reduced Dex starting dose (Rev/Vel 25/1.3, Dex 20 mg in all cycles). Toxicities were graded by NCI CTCAE v3.0. Pts with G>2 peripheral neuropathy (PNY) were excluded. Responses were assessed by modified EBMT and Uniform criteria. Pts with CR/nCR/VGPR/PR could proceed to ASCT after ≥4 cycles. Results: 33 pts (median age 56 yrs, 55% men, 84% IgG MM, 47% with ISS Stage II/III) have been enrolled to date in dose levels 1–4 and 4M, respectively, including 10 pts enrolled at the maximum planned dose (Dose Level 4M). Pts have received a median of 5 cycles; 9 pts have completed all 8 cycles. Two DLTs of G3 hyperglycemia due to high dose Dex were seen in dose level 4. Dose reductions in cycle 2 and beyond have occurred in dose levels 1–4 for Rev in 9 pts, Vel in 7 pts, and Dex in 17 pts, with 3 dose reductions having occurred in dose level 4M. Toxicities to date have been manageable. Only 1 G4 toxicity (thrombocytopenia) has been reported, plus 1 G3 DVT (reversed with LMWH), and no G≥3 PNY has been seen. The response rate across all dose cohorts (CR/nCR+VGPR+PR: subject to confirmation) is currently 89% in 25/28 evaluable pts, including 35% CR/nCR/VGPR. After median follow-up of 3 mos, median DOR, TTP, PFS, and OS have not been reached; all responders except 1 remain in remission, with 2 pts proceeding to ASCT. Conclusions: Rev/Vel/Dex is very active and well tolerated in newly diagnosed MM pts. The maximum planned dose has been reached at Rev 25 mg, Vel 1.3 mg/m2, and Dex 20 mg, with Phase 1 enrollment now complete using the lower dose of Dex. Enrollment to the Phase 2 component is ongoing.

Clinical Activity of a Novel Multiple Tyrosine Kinase and Aurora Kinase Inhibitor, ENMD-2076, Against Multiple Myeloma: Interim Phase I Trial Results

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1957-1957 ◽  
Author(s):  
Sherif Farag ◽  
Shuhong Zhang ◽  
Attaya Suvannasankha ◽  
Jing Liang ◽  
Robyn O'Bryant ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Clinical Trial ◽  
M Protein ◽  
High Dose ◽  
Significant Activity ◽  
Dose Levels ◽  
Asymptomatic Elevation

Abstract Abstract 1957 Background: Despite recent improvements, MM remains incurable, indicating the need for continued investigation of novel agents. ENMD-2076 is a novel, orally active molecule that has been shown to have significant activity against Aurora and multiple receptor tyrosine kinases. Recently, we demonstrated that ENMD-2076 has significant pre-clinical in vitro and in vivo activity against MM cell lines and primary myeloma cells (Wang et al., Br J Haematol, 2010). Furthermore, ENMD-2076 inhibited critical pathways for MM cell survival and proliferation, including PI3K/AKT pathway with downregulation of survivin and XIAP, and Aurora A and B kinases, inducing G2/M cell cycle arrest, angiogenesis, and the FGFR3 pathway. We present the interim results of a phase I clinical trial of ENMD-2076 in patients with relapsed and refractory MM. Methods: An open label, single agent, dose-escalation dose safety and tolerability trial of ENMD-2076 is currently conducted in heavily pre-treated, relapsed and refractory MM patients who have previously failed standard therapy. Using a 3+3 design, dose escalation with ENMD-2076 is currently being studied at the doses: 150, 225, 325, 400 mg PO daily in 28 day cycles. Patients receive 28-day cycles according to safety and tolerability and absence of progression. Pharmacokinetics and pharmacodynamic studies, including effect on phosphorylated histone 3 (pH3) in purified bone marrow MM cells, effect on the PI3K pathway in peripheral blood mononuclear cells (PBMC), and circulating endothelial cell precursors are being investigated. Results: Currently, dose-escalation for the first three dose levels has been completed. Nine patients of median age 54 (range, 48–76) years were treated. There were 5 males and 4 females. The median number of prior regimens was 3 (range, 2–5), with 8 patients having failed high-dose melphalan and autologous stem cell transplantation. The most commonly observed toxicities included grades 1–2 anorexia (n=2), nausea (n=2), diarrhea (n=3), fatigue (n=3), asymptomatic elevation of amylase (n=3) and lipase (n=1), leucopenia (n=1), and heavy proteinuria (n=1). Grades 3 toxicities included hypertension (n=1), asymptomatic elevation of lipase (n=2), and thrombocytopenia (n=1). No dose-limiting toxicity was observed with all toxicities resolving promptly upon interruption or discontinuation of dosing. All patients treated on dose level 1 had progression of disease on treatment, 1 patient in dose level 2 had stabilization of disease, and 2 patients on dose level 3 had stable disease although with 21% and 19% reduction in serum M-protein after the first cycle. Significant increases in pH3 in MM cells were observed in 4 of 5 patients tested in dose levels 2 and 3. p-STAT3 and pGSK-beta were downregulated in PBMC in one patient, who also had a 19% reduction in M-protein. Conclusion: In the ongoing phase I clinical trial, ENMD-2076 appears safe and well –tolerated at the doses tested to date. Additional schedules are under investigation based on tolerability and correlative analyses. ENMD-2076 may hold promise as a treatment for MM and further study is warranted. Disclosures: Farag: EntreMed, Inc: Research Funding. Bray:EntreMed, Inc.: Employment. Sidor:EntreMed, Inc: Employment.

Clofarabine in Combination with High-Dose Cytarabine and Liposomal Daunorubicin in Pediatric AML: Results of a Phase 1B Combination Study By the ITCC Consortium

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 989-989 ◽  
Author(s):  
Christian M. Zwaan ◽  
Michael Dworzak ◽  
Thomas Klingebiel ◽  
Claudia Rössig ◽  
Guy Leverger ◽  
...  
Keyword(s):  
Renal Failure ◽  
Response Rate ◽  
Lung Infection ◽  
High Dose ◽  
Off Label ◽  
High Dose Cytarabine ◽  
Phase 1B ◽  
Candida Sepsis ◽  
Pediatric Aml ◽  
Expansion Cohort

Abstract Introduction: Relapsed/refractory pediatric AML has a poor prognosis. Chemotherapy using FLAG plus liposomal daunorubicine (FLAG-DNX) followed by stem-cell transplantation (SCT) is currently considered the standard in 1strelapse in Europe (Kaspers, JCO 2013), and ~results in ~40% survival. FLAG is based on potentiation of high-dose cytarabine (Ara-C) by fludarabine (Flu) by increasing Ara-CTP levels. Clofarabine (CLO) is a novel purine nucleoside analog, designed to have improved efficacy. Methods: We initiated a phase 1B study using a ‘3x3 design’ to define the optimal dose of CLO, replacing Flu in FLAG-DNX. Dosages consisted of Ara-C 2gr/m2/day (day 1-5), with escalation of DNX from 40 to 60 mg/m2/day (day 1, 3 and 5), and CLO from 20, 30 to 40 mg/m2/day (day 1-5) in 4 dose-levels (DL). At day 6 intrathecal Ara-C was administered. Patients with early 1st relapse, refractory 1st relapse and 2nd relapse of AML were eligible. Responding patients received a consolidation with CLARA-DNX or treated by investigator discretion. DL 5 was open for patients with early 1st relapse only, and dose-escalated DNX to 80 mg/m2. MTD was the primary endpoint. At the MTD the cohort was expanded to 10 patients. Hematologic DLTs were defined as count recovery in responding pts >42 days. Overall response rate (ORR) was defined as: partial remission (PR, 50% reduction BM blasts), no evidence of leukemia (NEL, <5% blasts, no regeneration), complete remission with insufficient recovery (CRi, platelets below 80/μl and neutrophils below 1000/μl) and complete remission (CR). Morphology was centrally reviewed by the AML-BFM SG in Hannover. The study is registered in the Dutch Trial Registry (nr. 1880), and was open in 14 ITCC/I-BFM-sites. Results: DL 1-4 accrued 29 AML patients (≥2nd relapse, n=8; refractory 1st relapse, n=11; early 1strelapse, n=10). Patients were treated at dose-level (DL) 1, n=4; 2, n=3; 3, n=12 (split in 3A and 3B); 4, n=10. Twelve patients had been transplanted prior to enrollment. In total 38 CLARA-DNX courses were administered. Median age was 8.8 years, 18 patients were male, median WBC at enrollment 8.7x10.9/l. 26 SAEs were reported, consisting of febrile neutropenia (n=14), typhlitis (n=1), lung-infection fungal (n=3), lung-infection bacterial (n=2), candida sepsis (n=1), streptococcal sepsis (n=2), rash (hand-foot skin reaction) (n=1), and tumor lysis/capillary leak syndrome (n=1), cardiovascular failure (n=1) and vomiting (n=1). Other grade 3-4 AEs reported consisted of abdominal pain, nausea and vomiting, diarrhea, anorexia. blood pressure changes, DIC, rash and renal failure. Three pts had bilirubin elevation (>2.5xULN, max 61 µmol/l); 8 transaminitis (> 100 U/l; max. 998U/l), 1 elevated creatinine (83µmol/l) and 1 renal failure, 5 low potassium (<3 mmol/l) and 3 low sodium (<130mmol/l). At DL 3A, DLTs (fungal infection) halted dose-escalation. Detailed analysis showed subclinical fungal infections prior to enrollment. A protocol amendment was issued requiring screening patients with CT-scan and serum-galactomannan. After enrolling DL3B this appeared to be safe (1 DLT of Candida sepsis out of 6 patients). One DLT occurred at dose-level 4 (sepsis). Time to recovery of peripheral blood values in patients with CR/CRi was median 30 days for neutropenia and 26 days for platelets. Considering outcome, the ORR was 59% in the 26 pts evaluable for response. In the 11 pts with refractory 1st relapse after FLAG the ORR was 38%. In the expansion cohort (10 pts in DL4) there was 1 CR, 7 CRi, 1 PR, and 1 early death. 18 pts were transplanted post clofarabine treatment (1 HLA-id, 13 MUD, 1 MFD, 2 haplo, 1 unkown). The median follow-up time of the 9 survivors was 16 months. The 1-year overall survival was 48±9%, and the 1-year EFS was 33±9%. Five patients were recruited in DL5. Two DLTs occurred in 2 pts, i.e. a severe pseudomonas cellulitis and a Gram-negative sepsis, and hence this cohort was closed. Conclusions: The RP2D of CLO in a CLARA/DNX course in relapsed/refractory pediatric AML is 40 mg/m2 combined with DNX 60 mg/m2 and Ara-C 2 gr/m2, excluding patients with evidence of prior subclinical fungal infection. This combination resulted in a high response rate in the expansion cohort. We observed responses in 38% of patients refractory to FLAG. This regimen therefore has greater anti-leukemic potential than FLAG. Acknowledgment: This study was financially supported by Sanofi, and by the KiKa-foundation grant nr. 26. Disclosures Zwaan: Sanofi: Research Funding. Off Label Use: Clofarabine is off-label for AML, and so is Daunoxome.

scholarly journals Phase 1 Study of Escalating Doses of Ibrutinib and Temozolomide, Etoposide, Liposomal Doxorubicin, Dexamethasone, Rituximab (TEDDI-R) with Isavuconazole for Relapsed and Refractory Primary CNS Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-13
Author(s):  
Mark Roschewski ◽  
Christopher Melani ◽  
Rahul Lakhotia ◽  
Stefania Pittaluga ◽  
James D. Phelan ◽  
...  
Keyword(s):  
Dose Level ◽  
Fdg Pet ◽  
Liposomal Doxorubicin ◽  
Fungal Infections ◽  
Brain Mri ◽  
Clinical Activity ◽  
High Dose ◽  
Cell Transplant ◽  
Bcr Signaling ◽  
Dose Levels

Background: Primary DLBCL of the CNS (PCNSL) relies on chronic active B-cell receptor (BCR) signaling. Ibrutinib targets BCR signaling through BTK inhibition (BTKi), which may also impair innate immunity. We showed that ibrutinib and temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab (TEDDI-R) induces durable remissions in relapsed/refractory PCNSL but 7 (39%) pts developed Aspergillus infections without fungal prophylaxis. Newer triazoles are effective against Aspergillus but inhibit ibrutinib clearance through CYP3A4. Isavuconazole has less effect on CYP3A4 and less hepatotoxicity than voriconazole. We hypothesized that ibrutinib and isavuconazole could be safely co-administered in TEDDI-R and ameliorate the risk of Aspergillus while maintaining efficacy. We studied escalating doses of ibrutinib in TEDDI-R with isavuconazole to determine the safety profile, ibrutinib PK, and clinical activity in relapsed/refractory PCNSL. Methods: Pts with relapsed/refractory PCNSL, age ≥18, ECOG PS ≤2, and adequate organ function were enrolled. Previous BTKi, HIV, EBV+, and pregnancy were excluded. Pts had baseline MRI brain, FDG-PET brain and body, Ommaya placed, CSF with flow cytometry, and eye exam. Isavuconazole 200mg BID x 3d started prior to ibrutinib then 200mg daily. Three dose levels of ibrutinib (280mg, 420mg, 560mg) were given continuously through each cycle. Pts received up to 6 cycles of TEDDI-R with IT cytarabine. No one received maintenance or consolidation. If a DLT occurred in the first 3 pts at a given ibrutinib dose level, 3 more pts were treated before escalating. Full safety and PK data was reviewed after two dose levels prior to escalating. An expansion of 10 pts was planned at the highest ibrutinib dose level to confirm safety and clinical activity. Surveillance for fungal infections included chest CT mid-cycle 1 and after each cycle along with Beta-D glucan and aspergillus galactomannan in blood and CSF. Brain MRI was performed after cycles 1, 2, 4, and 6 to determine response and screen for CNS Aspergillus. All remissions by MRI were confirmed with FDG-PET and CSF analysis. Surveillance brain MRI were q3m for 1y, q4m x 1y, q6m x 1y, then annually. Primary objective was to identify the highest dose of ibrutinib safely co-administered with isavuconazole in TEDDI-R that achieves adequate PK concentrations. Results: 13 relapsed/refractory PCNSL pts enrolled between 11/2018 and 06/2020. 10 (77%) pts were male and the median age was 65 (range 46-77), including 3 pts ≥age 70. 13 (100%) pts had prior high-dose MTX, and 2 (15%) pts had prior autologous stem cell transplant (ASCT). Three evaluable pts received ibrutinib 280mg, 3 pts received ibrutinib 420mg, and 6 pts received ibrutinib 560mg. One pt in the 280mg cohort was not evaluable. Toxicity was evaluated in 13 pts across 49 cycles and the toxicity was mainly hematologic. G3 and G4 neutropenia occurred in 45% and 37% of cycles, respectively, while febrile neutropenia occurred in 8% of cycles. The median (range) duration of neutropenia was 4.5 (1-12) days. One pt with prior ASCT stopped after 4 cycles due to myelosuppression. Four (8%) cycles were complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. G3 and G4 thrombocytopenia occurred in 22% and 8% of cycles, respectively, and 1 pt developed melena with no overt GI bleeding. ≥G3 mucositis occurred in 6% of cycles and 1 patient stopped therapy after 5 cycles due to recurrent mucositis. Palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 9 (69%) pts, but only 1 G3 event occurred. Twelve pts were evaluable for response, and 11 (92%) pts have responded and all after receiving only 1 cycle (Figure 1). All 8 (100%) pts who have completed at least 4 cycles have achieved CR and the other 4 remain on therapy. Six (75%) pts who achieved CR remain in remission while 2 (25%) pts relapsed within 3 months of stopping therapy. After a median potential f/u of 5.2 months, the 1-year PFS is estimated at 60.0% (95% CI, 12.6-88.2) and the OS is 100%. Conclusions: Ibrutinib 560mg was safely co-administered with isavuconazole in TEDDI-R for relapsed/refractory PCNSL. No DLTs were observed, no cases of Aspergillus occurred, and no new safety signals. The first 8 (100%) patients who have completed therapy achieved complete response. Updated clinical results from this ongoing study (NCT02203526) will be presented at the meeting. Disclosures Lai: Abbvie: Consultancy; Agios: Consultancy; Jazz: Speakers Bureau; Macrogenics: Consultancy; Astellas: Speakers Bureau.

scholarly journals 483 Initial safety results and immune responses induced by a novel human papillomavirus (HPV)-specific gorilla adenovirus immunotherapy vaccine, PRGN-2009, in patients with advanced HPV-associated cancers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A513-A513
Author(s):  
Charalampos Floudas ◽  
Julius Strauss ◽  
Clint Allen ◽  
Renee Donahue ◽  
Caroline Jochems ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Hpv 16 ◽  
Dose Levels ◽  
Hpv 18

BackgroundPRGN-2009 is a novel gorilla adenovirus vaccine containing 35 non-HLA-restricted epitopes of HPV 16 and 18 which is being tested in an open-label, NCI-sponsored, single-center Phase I/II study alone and combined with the bifunctional TGF-β ”trap”/anti-PD-L1 fusion protein bintrafusp alfa (BA) (NCT04432597).MethodsFor the Phase I of the trial, eligible patients are adults with previously treated (checkpoint blockade allowed) recurrent/metastatic HPV-associated cancers. Objectives are to assess the safety and determine the recommended phase 2 dose (RP2D) of PRGN-2009 alone and combined with BA. Treatment followed a single-agent 3+3 dose escalation at two dose levels of PRGN-2009 (dose level 1: 1x1011 viral particle units (VPU), dose level 2: 5x1011 VPU) subcutaneously Q2W for 3 times, then Q4W for up to one year in total. After determination of RP2D, a combination cohort of 10 patients treated with PRGN-2009 at the RP2D combined with BA (1200 mg IV Q2W for 52 weeks) opened. Peripheral blood mononuclear cells collected from patients before and after vaccination with PRGN-2009 were stimulated with overlapping peptide pools and assessed by intracellular cytokine staining to identify HPV-16 and HPV-18 specific T-cells, as well as T-cells targeting cascade antigens not encoded by the vaccine.ResultsSix patients were enrolled in the single-agent PRGN-2009 dose-escalation phase (3 with cervical cancer, 2 with anal cancer, 1 with vaginal cancer). Observed adverse events were Grade 1-2 flu-like syndrome (headache, body aches), injection site reactions (erythema, pruritus, soreness, localized edema), fatigue, and rash. There were no dose limiting toxicities, and 5x1011 VPU was selected as RP2D. Four patients had stable disease as best response, (one ongoing, 10 months on treatment).T-cells targeting HPV-16 and/or HPV-18 were increased after vaccination in 100% of patients, with 3/6 (50%) developing HPV-16 T cells and 5/6 (83%) developing HPV-18 T cells. In some patients, the magnitude and breadth of HPV-16 and HPV-18 specific T cells were notably increased after repeated vaccination. T cells that target the cascade antigens brachyury and MUC1 were also increased in all patients evaluated. Multifunctional T-cell responses against all these antigens were also developed after vaccination in the majority of patients. No differences in immunogenicity were noted between the two dose levels. Enrollment is underway in combination with BA. Updated data will be presented.ConclusionsThe Phase 1 results demonstrate the safety of single-agent PRGN-2009 and induction of anti-HPV T-cell immune responses, supporting the hypothesis that PRGN-2009 could potentially induce anti-tumor effects in HPV-associated cancers.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NIH, NCI.Trial RegistrationNCT04432597Ethics ApprovalApproved by the NIH IRB (Ref No 543876). All participants have given informed consent before taking part in the study.

scholarly journals Interim Results of a Phase I Study of Lenalidomide (CC-5013) Plus Intraventricular/Intravenous Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4470-4470 ◽  
Author(s):  
James L. Rubenstein ◽  
Paul Formaker ◽  
Xiaomin Wang ◽  
Nianhang Chen ◽  
Michael Seider ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Intravenous Infusion ◽  
Phase I Study ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Comprehensive Cancer Center ◽  
Cns Lymphoma ◽  
High Dose ◽  
Dose Levels

Abstract BACKGROUND: There is an unmet need for effective therapies for relapsed/refractory primary and secondary central nervous system (CNS) and intraocular lymphomas (IOL), complications that are increasing in frequency among patients age >60. Whole brain irradiation, broadly utilized in the relapsed setting, yields insufficient efficacy and considerable morbidity, particularly in older patients. Implementation of new agents that selectively target survival pathways upregulated in refractory CNS lymphoma would have significant impact. Lenalidomide (CC-5013) has established activity as a single agent in aggressive NHL, particularly in ABC-type DLBCL. We recently demonstrated the activity of lenalidomide, at modest doses, in the treatment of recurrent/refractory intraocular and CNS lymphoma (J. Clin Oncol, 2011). We also provided evidence of cereblon-dependent efficacy of lenalidomide in preclinical models of patient-derived CNS DLBCL (ASH, 2013). These observations are the basis for this first trial of IMiD® immunomodulatory compound therapy in CNS NHL, as monotherapy, and in patients with inadequate responses to lenalidomide, in combination with combined intravenous plus intraventricular rituximab. (NCT01542918). METHODS: The primary objective of this phase I study is to evaluate the safety and efficacy of lenalidomide at three dose levels (10, 20, and 30mg) in relapsed/refractory CD20+ CNS NHL, with staging evaluations involving brain, CSF and intraocular compartments. Key secondary endpoints include: (1) determination of extent of CSF penetration by lenalidomide; (2) feasibility and activity of combined intraventricular and intravenous rituximab plus lenalidomide in patients with recurrent CNS lymphoma, not responsive to lenalidomide monotherapy; (3) evaluation of the effects of lenalidomide on the tumor microenvironment, including effects on tumor metabolism and immune cell infiltration and phenotypes. RESULTS: Thus far, seven subjects with relapsed CNS DLBCL (6 PCNSL, 1 SCNSL) have been treated on protocol at UCSF (median age 63, range 46-77). Each had methotrexate-resistant disease and 4 had lymphoma refractory to high-dose chemotherapy. In general, lenalidomide has been well-tolerated in the CNS lymphoma population with one DLT (non-hematologic) noted at the 20 mg dose level: fatigue and memory loss. Clinical benefit has been noted in 3 out of 4 patients with IOL, with 1 PR > 6 months duration and 1 SD > 10 months duration, each to lenalidomide monotherapy. Brain parenchymal responses to lenalidomide monotherapy (20 mg) have been demonstrated at restaging MRI, including 1 CR and 1 PR. There has been 1 CR in the leptomeninges with resolution of B-cell lymphoma in CSF, quantified by serial flow-cytometry. Combined intraventricular (20 mg) plus intravenous infusion of rituximab was well-tolerated in 3/3 patients and, with 10 mg lenalidomide, resulted in 1 PR in highly refractory IOL. Using GC/MS, we demonstrated lenalidomide penetration in ventricular CSF (0.6-7.9 ng/ml) in each of 4 patients, 12-15 hours after dosing at the 20 mg level, but trough lenalidomide concentrations >0.5 ng/ml were detected in only 1 of 3 patients receiving 10 mg lenalidomide. Serial metabolomic profiling revealed that CSF lactate correlated with clinical response to lenalidomide. Finally, we demonstrated that lenalidomide is reproducibly associated with a rapid and reversible effect on peripheral blood macrophage polarization to an M1, iNOS+ phenotype. CONCLUSIONS: These preliminary results provide evidence that lenalidomide is well-tolerated at 10 and 20 mg dose levels in CNS lymphoma. We demonstrate for the first time lenalidomide penetration in ventricular CSF, with higher trough concentrations detected at 20 mg compared to the 10 mg dose level. Encouraging evidence of lenalidomide efficacy in relapsed CNS DLBCL has been demonstrated in intraocular, CSF and brain compartments. Combined intraventricular and intravenous infusion of rituximab is feasible and represents a novel strategy to the potentiation of immunotherapeutic strategies in brain tumors. Studies are in progress to further elucidate the safety, pharmacokinetics and mechanisms involved in this biological approach to the treatment of refractory CNS lymphomas. Supported by NCI, Leukemia and Lymphoma Society, UCSF Helen Diller Comprehensive Cancer Center, Celgene and Genentech Disclosures Off Label Use: Intrathecal administration of rituximab. Wang:Celgene: Employment. Chen:Celgene: Employment.

Phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with tofacitinib in patients with advanced pancreatobiliary cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3051-3051
Author(s):  
Nebojsa Skorupan ◽  
Mehwish Iqra Ahmad ◽  
Guillaume Joe Pegna ◽  
Cody J. Peer ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Single Agent ◽  
Primary Objective ◽  
Pseudomonas Exotoxin A ◽  
Recombinant Immunotoxin ◽  
Level 1 ◽  
Expansion Cohort ◽  
Almost All

3051 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload to tumors. Previous clinical trials demonstrated that almost all patients formed anti-drug-antibodies (ADAs) to LMB-100 that made administration beyond cycle 2 ineffective. Tofacitinib is an oral JAK inhibitor that prevented formation of ADAs against a closely related immunotoxin in pre-clinical studies. The primary objective of the dose escalation cohort was assessment of safety and tolerability of LMB-100 given with tofacitinib to patients with mesothelin-expressing solid tumors. The primary objective of the expansion cohort was to determine whether co-administration of tofacitinib delays formation of neutralizing LMB-100 ADAs. Methods: Patients (n = 13) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; cholangiocarcinoma, appendix, cystadenocarcinoma) were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 mcg/kg) and co-treated with oral tofacitinib for the first 10 days of the cycle (10 mg BID). Results: Dose level 1 of LMB-100 was started at 100 mcg/kg one dose level below the single agent MTD. Dose escalation to 140 mcg/kg (dose level 2) resulted in DLTs in 2 of the 3 patients treated: grade 3 cardiac toxicity and grade 4 hyponatremia, both attributed to capillary leak syndrome. Ultimately, 7 patients were treated at dose level 1 without DLTs and 100 mcg/kg was chosen as the LMB-100 dose for the expansion cohort. The last of 6 patients treated in the expansion cohort developed grade 4 pericardial effusion leading to early closure of the study for toxicity. No objective responses were seen. Of the 8 patients who received two cycles of treatment at MTD, 4 met prespecified criteria for ADA prevention, and 2 patients who went on to receive cycle 3 had detectable LMB-100 plasma drug levels after administration. Conclusions: LMB-100 was unable to be co-administered safely with tofacitinib. ADA formation was prevented in 2 patients through 3 cycles, a rare occurrence. Clinical trial information: NCT04034238.

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 907-907 ◽  
Author(s):  
Udo Vanhoefer ◽  
Andreas Harstrick ◽  
Claus-Henning Köhne ◽  
Wolf Achterrath ◽  
Youcef M. Rustum ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Advanced Colorectal Cancer ◽  
High Dose ◽  
Weekly Schedule ◽  
First Line ◽  
Dose Levels ◽  
Line Chemotherapy

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Treatment with Bendamustine, Thalidomide and Prednisolone (BPT) in Patients with Refractory or Relapsed Multiple Myeloma after Autologous Stem Cell Transplantation or Conventional Chemotherapy: Results of a Phase I Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3564-3564 ◽  
Author(s):  
Wolfram Poenisch ◽  
Marta Rozanski ◽  
Hartmut Goldschmidt ◽  
Franz-Albert Hoffmann ◽  
Thomas Boldt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Dose Level ◽  
Single Agent ◽  
Fixed Dose ◽  
Maximal Response ◽  
High Dose ◽  
Conventional Chemotherapy ◽  
Who Grade ◽  
Treatment Regimens

Abstract Thalidomide is an active single agent in advanced relapsed or refractory multiple myeloma (MM). The combination of low dose thalidomide with bendamustine and prednisolone might maintain or increase efficacy of the drug while avoiding dose limiting toxicity (DLT). Patients and Methods: The treatment consists of a fixed dose of bendamustine (60mg/qm) day 1, 8, and 15 with prednisolone (100 mg) day 1, 8, 15, and 22. In addition, thalidomide is given in three escalating doses, starting with 50 mg to a maximum of 200 mg daily. At each dose level 8 to 12 relapsed or refractory patients, half of them after conventional chemotherapy and half after high dose therapy with stem cell support, were enrolled. Cycles were repeated every 28 days for a minimum of 2 and a maximum of 10 cycles either until a maximal response was achieved, or until a DLT or a disease progression were observed. Between March 2004 and May 2006, 28 patients were enrolled: 8 in the first dose level with 50 mg thalidomide; 8 in the second dose level with 100 mg and 12 in the third dose level with 200 mg. All patients had received a minimum of 2 prior treatment regimens. Seven patients had been refractory to the last treatment. Median age was 67 years (range: 40 – 78). All patients completed 2 cycles of BPT-treatment and are therefore evaluable. Response was assessed using EBMT criteria modified to include near complete remission (nCR) and very good partial remission (VGPR). Results: Twentyfive of 28 patients responded after at least 2 cycles of chemotherapy with 3 CR, 1 nCR, 5 VGPR, 15 PR and 1 MR. Two patients had stable disease and one patient was refractory. With a median follow up of 15 months, EFS and OS at twelve months were 34 % and 92 %, respectively. The most common side effects were constipation (11 patients WHO grade 1, 8 patients WHO grade 2), polyneuropathy (15 patients WHO grade 1, 3 patients WHO grade 2) and somnolence (4 patients WHO grade 1). None of the 28 patients developed dose-limiting hematoxicity as defined by an ANC < 1,0 Gpt/l for > 7 days or an ANC < 0,5 Gpt/l for > 3 days or platelet count < 25 Gpt/l. Transient neutropenia was reported in 9 patients (WHO grade 3 and 4) but no thrombocytopenia was observed. Conclusion: BPT with a dose between 50 and 200 mg thalidomide daily is well tolerated in patients with relapsed or refractory MM.

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