A phase 1 study of daily oral perifosine (P) with weekly paclitaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13117-13117 ◽  
Author(s):  
B. Ebrahimi ◽  
J. J. Nemunaitis ◽  
R. Shiffman ◽  
R. Birch ◽  
M. Diaz-Lacayo ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
Prior Chemotherapy ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Reductions

13117 Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) & T (80 mg/m2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the activity of the combination. [Table: see text] [Table: see text]

A phase 1 study of daily oral perifosine (P) with every 3-week paclitaxel (T)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13134-13134 ◽  
Author(s):  
T. F. Goggins ◽  
J. J. Nemunaitis ◽  
R. Shiffman ◽  
R. Birch ◽  
D. H. Berdeaux ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
State Level ◽  
Hematologic Toxicity ◽  
Ecog Performance Status ◽  
Full Dose ◽  
Phase Ii Studies ◽  
Grade 3

13134 Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination. [Table: see text] [Table: see text]

A phase 1 study of daily oral perifosine (P) and weekly gemcitabine (G)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13084-13084 ◽  
Author(s):  
S. Weiss ◽  
J. J. Nemunaitis ◽  
M. Diaz-Lacayo ◽  
R. Birch ◽  
B. Ebrahimi ◽  
...  
Keyword(s):  
Phase 1 ◽  
Performance Status ◽  
State Level ◽  
Unknown Primary ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Phase Ii Studies ◽  
Grade 3

13084 Background: Miltefosine (M) has been shown to be synergistic with gemcitabine (G) in vitro (Georgieva Cancer Letters 182: 163–174, 2002). Perifosine (P) is a derivative of M with less GI toxicity. Methods: Twenty-two patients (pts) were enrolled on a phase 1 study to determine if G could be given at a dose of 1000 mg/m2 on days 1 and 8 of a 21-day cycle with 50 mg of P given orally 1, 2 or 3 times a day on days 1–14. Three pts were entered at each dose and the cohort expanded to 6 if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Ten additional pts were entered at the highest dose achieved. Results: Disease sites: lung 6, pancreas 3, breast 3, renal 2, sarcoma 2, other 5. The median age was 61 (range 29–82); 11 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 3, range 1–4) & 6 had received prior G. 10 pts had received prior radiotherapy. The grade 3/4 non hematologic toxicities for each cohort are given in the table below: One pt on cohort 3 died from pneumonia and sepsis unrelated to therapy after cycle 1. A median of 4 cycles (range 1 - 18) were delivered. At each dose 50% of pts had no G dose reductions. P doses were reduced in 7% of cycles (50 mg - 5%, 100 mg - 15%, 150 mg - 7%). Fifteen pts were evaluable & 4 partial responses (lung, breast, pancreas and unknown primary) were seen; 6 pts had stable disease (renal (2), sarcoma (2), liver and head/neck) for a median of 6 (range 3 - 9) months. No responder had received prior G. Pharmacokinetic (PK) studies showed that the steady state level at 150 mg was 9.47 ± 4.56 μM compared to 10.14 ± 2.02 μM in an earlier study (Crul, Eur. J. Cancer 38: 1615–21, 2002) when this dose of perifosine was used alone. Conclusions: It is concluded that full dose G can be safely administered with perifosine doses up to 150 mg with manageable toxicity and without affecting the PK of P. Phase II studies are warranted to further define the activity of the combination and the contribution of P. [Table: see text] [Table: see text]

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.

Phase I study of vemurafenib (VEM) and cobimetinib (COB) with heat shock protein 90 (HSP90) inhibitor XL888 in advanced BRAFV600 mutant melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9553-9553
Author(s):  
Zeynep Eroglu ◽  
Ann Chen ◽  
Jiannong Li ◽  
Joseph Markowitz ◽  
Andrew Scott Brohl ◽  
...  
Keyword(s):  
Immune Cell ◽  
Phase 1 ◽  
Kidney Injury ◽  
Heat Shock Protein 90 ◽  
Maximum Tolerated Dose ◽  
High Response Rate ◽  
Phase 1 Study ◽  
Stromal Fibroblasts ◽  
Grade 3 ◽  
Dose Reductions

9553 Background: Resistance to BRAF+MEK inhibitors(i) in BRAF-mutant melanoma is common. Multiple resistance mechanisms involve HSP90 clients, and a phase 1 study of VEM with XL888 showed PFS rates similar to the combination of BRAF+MEKi (Eroglu, CCR, 2018). Methods: Combination of VEM (960 mg PO BID) and COB (60 mg QD for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60 or 90 mg PO twice weekly) was investigated in a phase 1 study of advanced melanoma, with a modified Ji dose escalation design. Dose-limiting toxicity (DLT) was defined as related grade ≥3 adverse event or inability to deliver 75% of XL888 in first 4 weeks. Results: 25 pts (9 female, median age 62, 15 with M1C disease, 6 with prior anti-PD-1 therapy) were enrolled. After 2 DLTs (rash and acute kidney injury) in first cohort, a lower dose of VEM 720 mg BID and COB 40 mg, with the same XL888 cohorts was investigated. 3 DLTs (rash) in 12 pts were observed in the XL888 60 mg cohort, which was determined as the maximum tolerated dose. Most common grade 3 toxicities included diarrhea (8), hypertension (6), rash (5), alkaline phosphate/GGT elevation (4). 11 patients required dose reductions of VEM and/or COB. Objective responses (PR/CR) were observed in 18 of 25 pts (72%; 95% CI: 51-88%). Median PFS was 8.1 months (4.7 – NA); median overall survival was not reached, with 1-year OS of 71% (45-86%). Single cell RNA-Seq (10X genomics) was performed on baseline and on-treatment tumor biopsies; 8 days of treatment was associated with an increase in immune cell influx (CD4+ and CD8+) and a decrease in number of melanoma cells. At day 8, one patient (now without progression for nearly 2 years) had no tumor cells remaining with only immune cells and stromal fibroblasts left. Further analyses will be presented. Serial plasma BRAF circulating tumor (ct)DNA levels were obtained, with decrease in ctDNA levels corresponding with response and 83% of patients with disease progression showing an elevation in ctDNA from baseline. Conclusions: VEM/COB plus XL888 had significant toxicity, requiring dose-reductions that may have contributed to the low PFS rate despite high response rate. Caution must be used in combination of BRAF+MEKi with other agents. Clinical trial information: NCT02721459.

scholarly journals Phase 1 Study of Bisthianostat, an Orally Efficacious Pan-HDAC Inhibitor: Part Results of Safety, Pharmacokinetics and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5591-5591
Author(s):  
Hong-Hui Huang ◽  
Jian Hou ◽  
Yang-Ming Zhang ◽  
Yu-Bo Zhou ◽  
Li Jia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Hdac Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Human Study ◽  
Weekly Schedule ◽  
Phase 1 Study ◽  
Expansion Phase ◽  
Grade 3

Background: Multiple myeloma (MM) is the second most common hematological malignancy. This disease remains incurable as nearly all patients will relapse and become refractory to established MM therapy. Thus, new treatment option for relapsed or refractory (R/R) MM is needed, particularly those with different mechanisms of action. One such approach is to inhibit histone deacetylase (HDAC) and produce synergistic anti-myeloma activity via mechanisms of epigenetic modulations. In 2015, panobinostat was approved by US FDA as the first HDACi to treat R/R MM in combination with bortezomib and dexamethasone. Bisthianostat is a novel bisthiazole-based HDACi evolved from the thiazole-thiazoline cap group in natural product Largazole (Nan et al., ACS Med Chem Lett. 2014). It is orally available and displayed inhibition against a series of MM cell lines. Here we presented preliminary in-human findings from CH-020PI study, an ongoing phase 1 study of bisthianostat. (Trial registered at ClinicalTrial.gov: NCT03618602) Methods: CH-020PI is a first-in-human study to investigate the safety, tolerability, pharmacokinetics, and efficacy of bisthianostat in R/R MM patients. It is a single center, open-label, single arm, dose escalating phase I study. A standard 3+3 cohort design with 100mg as the starting dose was used to determine the maximum tolerated dose of bisthianostat. This study comprised two phases: a pharmacokinetics phase and an expansion phase. In the pharmacokinetics phase, a single-dose of bisthianostat was administered on day 1, and then multiple-dose was administered on a twice-weekly schedule for 4 consecutive weeks. Patients in the expansion phase received continuous bisthianostat twice weekly until progressive disease or unacceptable toxicities. Results: Until 30 June 2019, 8 patients were enrolled at 3 dose levels from 100 to 400mg. The median age at enrollment was 62 years (range, 51-70 years). The median number of previous lines of therapy was 5 (range, 2-6). Per protocol, all of 8 patients were evaluable for pharmacokinetics, toxicities and efficacy. In the pharmacokinetic evaluation, for all the 8 patients tested at day 1, the peak concentration of bisthianostat was reached within 2.3 hours; half life time were around 4 hours; bisthianostat uptake represented by AUClast were in good proportion to the level of dose as 100, 200 and 400mg, respectively. Similar results were observed at day 28. Any grade hematological treatment-related adverse events (AEs) occurred in 4 of 8 patients (50%), while grade 3/4 hematological AEs occurred in 2 (25%) patients. Any grade non-hematological treatment-emergent AEs were observed in 3 (37.5%) patients; no grade 3/4 non-hematological AEs were reported. No patient discontinued the treatment of bisthianostat due to AEs. Except patient 007 (200mg cohort) experienced a grade 2 nausea, no patients experienced diarrhea, nausea, or vomiting. It is worthy to note that gastrointestinal toxicity is common with the use of panobinostat, a FDA-approved HDAC inhibitor. Overall single-agent efficacy was modest, and stable disease (SD) was observed in 4 (50%) patients. At the time of data cut-off for statistical analysis, no dose-limiting toxicity has been observed. Conclusions: Bisthianostat proved to be well absorbed and tolerated. It exhibited modest anti-tumor efficacy in our cohort of heavily pretreated patients with R/R MM. This phase I clinical trial is currently ongoing, and future trials should compare different doses and schedules of the combination in order to optimize the treatment tolerability and enhance its efficacy. Disclosures No relevant conflicts of interest to declare.

Safety and tolerability of oxaliplatin based pressurized intraperitoneal aerosol chemotherapy (PIPAC) for patients with peritoneal carcinomatosis: A phase I dose-finding study in Asian patients.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 360-360 ◽  
Author(s):  
Raghav Sundar ◽  
Guo Wei Kim ◽  
Hon Lyn Tan ◽  
Lingzhi Wang ◽  
Koy Min Chue ◽  
...  
Keyword(s):  
Peritoneal Carcinomatosis ◽  
Dose Escalation ◽  
Intraperitoneal Chemotherapy ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 1 Study ◽  
Dose Cohort ◽  
Asian Patients ◽  
Delivery Technique ◽  
Grade 3

360 Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m2; 150mg/m2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m2. Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m2, necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m2) tolerated PIPAC well. Nine patients who underwent a 2nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m2. Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.

Voreloxin (formerly known as SNS-595) in Combination with Cytarabine Demonstrates Preliminary Clinical Responses in a Phase 1 Study in Relapsed/Refractory Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1955-1955 ◽  
Author(s):  
Jeffrey Lancet ◽  
Judith E. Karp ◽  
Larry D. Cripe ◽  
Gail J. Roboz ◽  
Matt Suster ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Phase 1 Study ◽  
Patient Response ◽  
Clinical Responses ◽  
Phase 1B ◽  
Grade 3 ◽  
Refractory Aml

Abstract Background: Voreloxin (formerly SNS-595) is a first-in-class replication-dependent DNA damaging agent that causes apoptosis by DNA intercalation and inhibition of topoisomerase II. A previous phase 1 study of single-agent voreloxin demonstrated acceptable safety and strong signs of clinical activity in patients with relapsed/refractory hematologic malignancies (ASH 2007), where MTD was found to be 72 mg/m2 weekly x 3 and 40 mg/m2 twice weekly x 4. In nonclinical models, the combination of voreloxin and cytarabine demonstrated enhanced activity. Preliminary results of an ongoing phase 1b study of combination voreloxin plus cytarabine in relapsed/refractory AML patients are reported. Objectives: establish safety, tolerability and MTD of escalating doses of voreloxin combination with continuous infusion cytarabine, characterize voreloxin PK in the setting of cytarabine given as a continuous intravenous infusion (CIV) assess clinical activity explore markers of patient response evaluate ex vivo voreloxin sensitivity in bone marrow as a predictor of response. Methods: Open label, doseescalation phase 1b study with a starting dose of voreloxin of 10 mg/m2 (given on days 1,4) in combination with 400 mg/m2/day CIV cytarabine for five days. Dose-limiting toxicities (DLTs) were assessed during cycle 1. PK analyses for voreloxin were performed during cycle 1. Pre- and post-dose PBMC were obtained to evaluate modulation of DNA damage response markers as correlates of patient response. Ex vivo sensitivity to voreloxin of baseline bone marrow samples was evaluated using the CellTiter-Glo® proliferation assay. Clinical response was determined based on IWG criteria. Patients could receive up to 2 courses of induction, and patients achieving CR or CRp could receive up to 2 courses as consolidation. At MTD, an additional cohort of patients will be enrolled to further assess safety. Results: To date, 26 patients have been enrolled and 24 have received treatment. Demographics: 16 males, 8 females, median age 61.4 years (range 30 – 74.5 yrs). Disease status: 17 of 24 treated patients had relapsed disease. Median number of prior therapies was 2 (Range 0–4). Two patients had prior allogeneic stem cell transplant. Dose escalation has proceeded to 80 mg/m2/dose (cohort 6). Safety: a single DLT has been observed (grade 5 septic shock in one patient treated at 70 mg/m2). Grade 3+ related non hematologic AEs ≥ 5% incidence: infections (23%). Grade 3+ hematologic toxicities have been consistent with past experience and include febrile neutropenia, anemia, and thrombocytopenia. The most common reason for early study termination was disease progression. Voreloxin pharmacokinetics were unaffected by cytarabine compared with the single agent phase 1 study. Preliminary clinical responses are listed below in Table 1. Conclusion: Voreloxin given in combination with continuous infusion cytarabine is generally well-tolerated, with encouraging signs of activity in patients with relapsed/refractory AML. Dose escalation continues. Table 1: Clinical Responses by Cohort Cohort Voreloxin Dose Treated/Enrolled DLTs Responses 1 10 4/4 0 0 2 20 3/4 0 1 CR 3 34 4/4 0 2 CR 4 50 6/6 0 2 CR 5 70 7/8 1 2 CR

Gemtuzumab Ozogamicin in Combination with Vorinostat and Azacitidine As Induction and Post-Remission Therapy in Older Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase 1 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1541-1541
Author(s):  
Roland B. Walter ◽  
Bruno C. Medeiros ◽  
Kelda M. Gardner ◽  
Elihu H. Estey
Keyword(s):  
Dna Methyltransferase ◽  
Phase 1 ◽  
Hdac Inhibitors ◽  
Gemtuzumab Ozogamicin ◽  
Hematologic Toxicity ◽  
Phase 1 Study ◽  
First Relapse ◽  
Grade 3 ◽  
Count Recovery

Abstract Abstract 1541 Background: The anti-CD33 immunoconjugate, gemtuzumab ozogamicin (GO), is efficacious in only a minority of AML patients when used alone. Emerging data suggest that epigenetic modifiers may chemosensitize to GO. For example, histone deacetylase (HDAC) inhibitors such as vorinostat increase CD33 expression and lower the apoptotic threshold to GO in vitro, while DNA methyltransferase I inhibitors such as azacitidine enhance GO efficacy in vitro and show promise when combined with GO in early clinical studies. These studies, together with the improved clinical activity when HDAC inhibitors are used with DNA methyltransferase I inhibitors, prompted a phase 1 study (NCT00895934) of GO with vorinostat and azacitidine for primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring 1st salvage therapy. Methods: Patients aged ≥50 years were eligible if they had an ECOG performance status of 0–3 and had adequate organ function. Patients with prior hematopoietic stem cell transplantation were eligible if relapse occurred 6–12 months post-transplant. Excluded were patients with a second active malignancy, prior treatment with any of the study drugs, or central nervous system disease. Hydroxyurea was given to reduce the total white blood cell count to <25,000/μL before treatment. Patients were assigned to therapy according to a “3+3” study design. If there was persistent leukemia (>20% blasts in non-hypoplastic bone marrow) on day 15, the first cycle was repeated, and patients came off study if, after repetition, there was disease progression. In all other patients, a second cycle was begun if peripheral blood counts had recovered (blood count recovery was not required for patients with persistent leukemia) and all toxicities had resolved to ≤grade 2. Patients came off study if a partial remission (PR; >50% decrease of bone marrow blast percentage) was not achieved by the end of cycle #3, or if a complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) was not achieved by the end of cycle #6. Dose-limiting toxicity (DLT) was defined as: 1) any grade 3 non-hematologic toxicity lasting >48 hours that results in >7 day delay of the subsequent treatment cycle, with the exception of febrile neutropenia or infection; 2) any grade ≥4 non-hematologic toxicity, with the exception of febrile neutropenia/infection or constitutional symptoms if recovery to grade ≤2 within 14 days; and 3) prolonged myelosuppression (platelet count <20,000/μL and/or absolute neutrophil count <500/μL at day 42 after treatment in patients without evidence of persistent leukemia). Results: 15 patients (8 male, 7 female), median age 65.7 (range, 50.2–69.8) years, with either primary refractory disease (n=6) or first relapse (n=9; median duration of first CR: 6 months) were enrolled on this study and received a median of 2 (range, 1–3) cycles of therapy (see Table): One DLT of death due to sepsis and respiratory failure occurred at dose level 4 after cycle 1, defining this level as maximum tolerated dose (MTD). Death within 8 weeks of therapy initiation occurred in 5 patients (33.3%). Besides grade 3–4 cytopenias, the most common grade33 adverse events were: neutropenic fever (n=8) or documented infection (n=5), hypoalbuminemia (n=3), and acute renal failure (n=2). As detailed in the table, 2 patients (13.3%) each achieved either a CR or a CRi for a total CR/CRi rate of 4/15 (26.7%); 2 additional patients (13.3%) met morphological criteria for CRi but had MRD (<5% abnormal blasts) by flow cytometry. Nine patients (60.0%) either had RD (n=8; 53.3%) or experienced DA (n=1; 6.7%). An exact 95% confidence interval about the CR rate is 0–32% compared to an expected CR rate of 15% in 1st salvage patients with CR durations of 0–12 months. Thus, the study is continuing (at dose level 4). Conclusion: The combination of GO, vorinostat, and azacitidine appears feasible and shows anti-AML activity in this cohort of difficult-to-treat patients. Disclosures: Off Label Use: The presentation discusses a phase 1 study using azacitidine, vorinostat, and gemtuzumab ozogamicin for treatment of adults with relapsed/refractory AML; none of these 3 drugs is currently approved for this use in the U.S. Medeiros:Celgene: Honoraria, Research Funding.

Rituximab +/− Bevacizumab for Patients with Previously Treated Follicular Non-Hodgkins Lymphoma: A Randomized Phase II Trial of the Sarah Cannon Research Institute.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2749-2749
Author(s):  
John D. Hainsworth ◽  
Dana S. Thompson ◽  
F. Anthony Greco ◽  
Eric Raefsky ◽  
Scott Lunin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Overall Response ◽  
Randomized Phase Ii ◽  
Previously Treated ◽  
Grade 3 ◽  
Tumor Types

Abstract Abstract 2749 Background: Single-agent rituximab produces an overall response rate of approximately 50% and a median PFS of 9 months in patients with previously treated follicular NHL. Since resistance to rituximab eventually develops in nearly all patients, a number of novel agents are currently being evaluated in combination with rituximab to improve treatment efficacy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and is increased in many tumor types. In NHL, high levels of VEGF are correlated with disease progression. Bevacizumab, a monoclonal antibody inhibiting VEGF, has extended PFS in several solid tumor types when added to combination chemotherapy. In this randomized phase II trial, we compared the efficacy and toxicity of bevacizumab + rituximab versus single-agent rituximab, in patients with previously treated follicular NHL. Methods: Eligible patients had follicular NHL (grade 1 or 2); NHL progression after either 1 or 2 prior chemotherapy regimens; measurable or evaluable disease; and ECOG PS 0–2. Prior rituximab treatment was allowed as long as progression occurred > 6 months following completion of treatment. Patients were randomized to receive single-agent rituximab (Regimen A) or rituximab plus bevacizumab (Regimen B). All patients received 375 mg/m2IV of rituximab weekly for 4 weeks. Regimen B patients also received bevacizumab 10 mg/kg IV on days 3 and 15 during the 4-week course of rituximab. Response evaluations were performed at weeks 6 and 12 as well as 4 weeks after the completion of all therapy. Patients with objective response or stable disease at week 12 received 4 additional doses of rituximab administered at months 3 (week 12), 5, 7, and 9; in addition, regimen B patients received bevacizumab 10 mg/kg IV every 2 weeks for a total of 16 doses (also beginning week 12). Addition of bevacizumab was hypothesized to improve the median PFS from 15 months to 20 months. Accrual of 90 patients (45/arm) was initially planned; the study was stopped early due to slow accrual. Results: Between 8/2005 and 3/2012, 60 patients were enrolled (Regimen A, 30; Regimen B, 29). Key clinical characteristics including age, performance status, FLIPI score, and previous treatment were comparable in the 2 treatment groups. 95% of patients had received 2 previous regimens, and 78% had received previous rituximab. After a median followup of 36 months, 92% of patients have either completed (40%) or discontinued treatment (lymphoma progression 30%, toxicity 12%, patient/physician decision 8%). The overall response rates were 42% in Regimen A (CR rate 10%) and 45% in Regimen B (CR rate 17%). The median progression-free survivals for Regimens A and B were 10.4 and 18.4 months, respectively (HR 0.33, p=0.0090). Median OS has not been reached for either group; at 3 years, the estimated OS rates are 54% (Regimen A) and 81% (Regimen B) (p=0.12). Grade 3/4 hematologic toxicity was uncommon, with no grade 4 neutropenia or thrombycytopenia, and 1 episode of febrile neutropenia (Regimen B). No grade 4 non-hematologic toxicity occurred; grade 3 non-hematologic toxicity occurred in 3 patients (10%) on Regimen A (infusion reaction 1, hyperglycemia 1, pneumonia 1) and 7 patients (24%) on Regimen B (hypertension 3, epistaxis 1, abdominal wall hematoma 1, wound dehiscence 1, confusion 1). All 7 patients who discontinued treatment due to toxicity (3 during the first 12 weeks) were on regimen B; 5 had bevacizumab-related toxicity. There were no treatment-related deaths. Conclusion: The addition of bevacizumab to rituximab was feasible with a modest increase in toxicity in this group of patients with previously-treated follicular NHL. The toxicities observed were consistent with the known profiles of each agent. While response rates were similar between regimens, the addition of bevacizumab lengthened the progression-free survival when compared to rituximab alone (median 18.4 vs. 10.4 months). Although results of this study must be interpreted with caution due to its small size, further study of VEGF- targeted therapies in NHL may be warranted. Disclosures: Off Label Use: Off-label bevacizumab use for treatment of follicular non-Hodgkin's lymphoma. Reeves:Celgene: Equity Ownership.

Perifosine (P) can be combined with docetaxel (T) without dose reduction of either drug

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13066-13066 ◽  
Author(s):  
A. Cervera ◽  
B. Bernhardt ◽  
J. J. Nemunaitis ◽  
B. Ebrahimi ◽  
R. Birch ◽  
...  
Keyword(s):  
Dose Level ◽  
Metastatic Prostate Cancer ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Ecog Performance Status ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Head Neck ◽  
Dose Reductions

13066 Background: Perifosine is an alkylphospholipid that modulates several signal transduction pathways, including Akt, which is often activated in taxane resistant tumors and is thought to be one mediator of such resistance. The combination of T, 75 mg/m2 every 3 weeks, and prednisone (Pr), 5 mg bid has become standard therapy for patients (pts) with metastatic prostate cancer. The addition of P might decrease resistance to T in these patients who often have activated Akt because of PTEN mutations. This phase I trial is the first attempt to combine these agents. Methods: Between 12/04 and 9/05, 39 pts were enrolled. P was given either daily as a 50 mg tablet 1, 2 or 3 times per day on days 1–14 or weekly in doses of 300 mg every 4 - 6 hours 3, 4 or 5 times on days 1–2, 8–9 and 15–16 of each 21 day cycle. T, 75 mg/m2, was given on day 8 of a 21 day cycle with or without Pr. Results: Disease sites: prostate 11, NSCLC 9, ovary 4, head/neck 3, pancreas 3, breast 2 & other 7. Median age was 63 (range 37–80); 24 patients were male and median ECOG performance status was 1 (range 0–2). 34 pts had received prior chemotherapy including 24 previously given a taxane. Three patients were entered at each dose level for each schedule and the cohort expanded to 6 patients if 2 or more patients experienced a grade 3/4 non-hematologic toxicity (DLT) during the first cycle of therapy. A dose level was toxic if 4 or more patients experienced a DLT during cycle 1. The grade 3/4 toxicities for each perifosine dosing schedule are given in the table . Glucose values for the grade 3 toxicities were between 253 and 306. This was seen only in the Pr pts & has not been observed in other P trials. P dose reductions were required in 4% of cycles for daily P, 5% for daily P+Pr and 37% for weekly P. Conclusions: Daily doses up to 150 mg could be administered either with or without Pr but the maximum tolerated dose for the weekly regimen was 1200 mg It is concluded that daily P ± Pr is well tolerated with T 75 mg/m2 q 3 weeks and that daily doses are preferred for phase II studies to further define activity of the combination. [Table: see text] [Table: see text]

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