Onyx Pharma $ONXX will present numerous studies on Carfilzomib, being developing for multiple myeloma. I will not post and analyze each one, however the data continue to be strong. Here is the link to ONXX's press release about the data. ONXX is guiding for the rolling NDA to be completely submitted in July or August 2011, indicating a likely FDA approval in early 2012. Carfilzomib utilizes Captisol formulation technology licensed from Cydex Pharma, which has since been acquired by $LGND. Ligand will receives milestones upon NDA acceptance, drug approval, plus royalties on sales and income from selling the raw Captisol material to ONXX.
Abstract 6623 presents phase 1 data for the CDK inhibitor dinaciclib (partnered to Merck $MRK via Schering Plough $SGP) in relapsed/refractory CLL. Overall, 15/33 pts had a PR (and 4 of these were able to proceed to allogeneic stem cell transplant) including 7/15 with a chromosome 17p deletion. At the recommended phase 2 dose, 10/16 pts had a PR. Median PFS had not yet been reached in this cohort. Safety was acceptable, will the most common DLT being tumor lysis syndrome (sometimes leads to needing kidney dialysis). Data from an additional cohort will be presented at the meeting.
Abstract 3080 presents final phase 1 data for dinaciclib in advanced solid tumors. 81 pts were treated, no RECIST responses but 10 pts had stable disease (SD) of at least 6 months. Very short half life of only a few hours.
Abstract 6632 shows that Promacta (eltronbopag) is able to expand the human and mouse hematopoietic stem cell and hematopoietic progenitor stem cell populations, which has potential utility in the area of umbilical cord blood transplatation, which is promising but this blood is low in stem cells.
Abstract 6571 presents phase 2a data for a Captisol formulation of melphalan (Alkeran) in patients with multiple myeloma undergoing autologous transplantation. This product with improved solubility, stability, and lack of propylene glycol, was able to achieve higher drug exposure at half the previous dose while preserving efficacy (measured as successful myeloablation and subsequent engraftment) and adding no toxicity.
Monday June 6th: Poster Presentation Abstract #6623
"Phase I study of the CDK inhibitor dinaciclib (SCH 727965) in patients (pts) with relapsed/refractory CLL."
Joseph M. Flynn, DO
Background: Dinaciclib is a potent and selective inhibitor of CDKs 1, 2, 5, and 9, with anti-CLL activity in ex vivo assays.
Methods: Phase 1 trial to determine the recommended phase 2 dose (RPTD) of dinaciclib in CLL pts as a 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. The 5 mg/m2 starting dose is based on significant CLL cell kill in preclinical assays.
Results: 33 pts treated in 5 dose cohorts (5, 7, 10, 14 and 17 mg/m2). RPTD is 14 mg/m2. Median age is 62 (43-79) yrs, 42% ≥65 yrs, 67% Rai stage 3 or 4, 64% bulky disease, and 45% del 17p. Median # of prior therapies is 4 (1-12). 91% received fludarabine. 36% received flavopiridol. Median # of treatment cycles given is 5 (1-16). 9 pts received 6-8 cycles. 5 pts received 10-16 cycles. 15 partial responses (PR) by 1996 NCI-WG CLL criteria, with 4 pts proceeding to allogeneic SCT. Responders included 7 pts >65 yrs, 9 bulky disease, 14 prior fludarabine, and 5 prior flavopiridol. PR in 62.5% of pts (10/16) at the RPTD. PR in 47% of del 17 pts (7/15). Pts followed to disease progression, death, or dropout. Of 33 treated pts, 24 censored (follow-up 3.1 to 73.0 weeks) without disease progression or death. 9 pts progressed or died with a time to event of 1.1 to 16.1 weeks. Median PFS not yet reached. Rapid decrease in MCL-1, in 25 of 27 pts assayed by Western blot, confirms PD activity. PK analysis shows dinaciclib is rapidly eliminated with t1/2 of 2.1 to 3.8 hrs. Exposure is dose related with no drug accumulation in plasma. Common treatment related adverse events include neutropenia, anemia, thrombocytopenia, hyperglycemia, hypocalcemia, increased AST, diarrhea, and leukopenia. DLTs of bacterial pneumonia and tumor lysis syndrome (TLS) requiring temporary dialysis were observed at 17 mg/m2. A 2nd case of TLS requiring dialysis occurred in the RPTD 10 pt expansion cohort. 5 cases of TLS, 2 requiring dialysis, have occurred. Data will be presented on an ongoing cohort of 6 pts to determine if a step-up from 10 mg/m2 Day 1 to 14 mg/m2 Day 8 reduces the occurrence of TLS.
Conclusions: Dinaciclib has an acceptable safety profile and demonstrates promising clinical activity in heavily pre-treated CLL patients with bulky disease or del 17p. Further studies, in CLL and related B-cell malignancies, are warranted.
Monday June 6th: Poster Presentation Abstract #3080
"A phase I study of the CDK inhibitor dinaciclib (SCH 727965) administered every 3 weeks in patients (pts) with advanced malignancies: Final results."
Monica M. Mita, MD
Background: Dinaciclib is a potent and selective inhibitor of CDKs 1, 2, 5, and 9 with anti-tumor activity in multiple tumor cell lines and xenograft models.
Methods: Dinaciclib is administered every 3 weeks in pts with advanced malignancies. Part 1: accelerated titration design to establish the RP2D of a 2-hr IV infusion. Part 2: 8 and 24-hr continuous IV infusions. Part 3: determined effect of the CYP3A4 inhibitor aprepitant on PK. PD assessments: ex vivo lymphocyte proliferation assay; FDG-PET/CT scans; and skin and/or tumor biopsies for IHC of cdk targets.
Results: 81 pts treated. Part 1: Doses 1.85 to 58 mg/m2. RP2D 50 mg/m2. DLTs: non-neutropenic sepsis (1), neutropenic fever (2), neutropenia with pneumonia (1), hypotension (1), and rise in transaminases (3). Part 2: 7.4 and 10.4 mg/m2 well tolerated as 8- and 24-hr infusions, respectively. DLTs seen at lower doses with 8-hr and 24-hr vs 2-hr infusions. 8-hr DLTs: neutropenia with or without fever (5), hypotension (1), syncope (1), and elevated transaminases (2). 24-hr DLTs: rise in bilirubin (1) and delirium (1). Part 3: pts received dinaciclib 29.6 mg/m2 by 2-hr infusion +/- aprepitant. Among all pts, the most common treatment-related adverse events were nausea, vomiting, diarrhea, neutropenia, and fatigue. Dinaciclib was rapidly eliminated with a t1/2 of 1.4-3.3 hrs. Coadministration of aprepitant had no significant effect on PK. PD: Dose and infusion time correlated with degree and durability of suppression of lymphocyte proliferation. Tumor metabolic changes occurred in some pts by FDG-PET at day 8 but were not predictive of response. No objective responses by RECIST; SD ≥6 cycles (range 6-30) achieved in 10 pts. Pre/post tumor biopsies from 2 pts with melanoma show reduced phospho-Rb [pT356] post-treatment; total Rb was preserved. In 1 pt, p27 and p53 increased post-treatment, consistent with cdk2 and cdk9 inhibition. Analysis of skin biopsies ongoing. Conclusions: Dinaciclib has an acceptable safety profile at 50, 7.4 and 10.4 mg/m2 for 2-, 8- and 24-hr infusions, respectively, without PK interaction with aprepitant. Prolonged SD was achieved in some pts. Trials are ongoing in hematologic malignancies and melanoma.
Monday June 6th: Poster Presentation Abstract #6632
"Effects of eltrombopag on human cord blood hematopoietic stem cell/primitive progenitor cell expansion."
Hongliang Sun, PhD
Background: Umbilical cord blood transplantation has emerged as a promising therapy but is low in stem cells. Agents enhancing expansion of CB hematopoietic stem cell (HSC)/hematopoietic progenitor cell (HPC) are highly desirable. Eltrombopag (epag) is a non-peptide, c-MPL agonist that activates c-MPL of human and chimps. We investigate effects of epag on expansion of HSC/HPC of human CB.
Methods: (1) In vitro: CB CD34+ cells were treated with rhTPO or epag in presence of rhSCF and rhFL for 7 days. After staining with anti-CD41, anti-CD34 and anti-CD38, cells were analyzed by Flow. (2) Intracellular signaling: serum-starved cells expanded from CB CD34+ were treated with rhTPO or epag. Phosphorylation of STAT3, STAT5 and AKT in c-MPL signal pathway was analyzed by Flow after staining with anti-phospho-STAT3, anti-phospho-STAT5, anti-phospho-AKT anti-CD41, anti-CD34, and anti-TPO-receptor. (3) In vivo: Sublethally irradiated NOD/SCID mice were transplanted with CB CD34+ and gavaged daily with epag or water (28 d) and sacrificed between 1-9 wks. Blood count and bone marrow (BM) extracts were analyzed by Flow after staining with anti-human-CD41a-PE, anti-mouse-CD61-FITC, anti-human-CD45-FITC, anti-mouse CD45-PE, anti-human-CD34-FITC and anti-human-CD41a-PE antibodies.
Results: (1) Epag increased CD34+ by 26%, CD34+CD38- by 42%, and CD41+ by 400% in culture, compared with130%,160% and 900%, respectively by rhTPO. The % CD34+, CD34+CD38- and CD41+ were similar comparing rhTPO with epag. (2) Both rhTPO and epag induced phosphorylation of STAT5 in CD34+CD41-, CD34-CD41+ and CD34-CD41- cells. rhTPO-induced pSTAT5 was cell-type dependent, while epag-induced pSTAT5 was not. rhTPO-induced the phosphorylation of STAT3 and AKT in CD34-CD41+ cells, while pSTAT3 and pAKT were not detectable in epag treated CD34-CD41+ cells. (3) Epag led to an increase of circulating human platelets and WBCs without affecting murine platelets or WBCs in NOD/SCID. Epag augmented expansion of human CD45+, CD34+ and CD41+ cells in BM without effects on mouse BM cells.
Conclusions: Eltrombopag expanded HSC/HPC of CB in vitro, promoted human platelet and WBC proliferation/differentiation in NOD/SCID mice, and human HSC/HPC in mouse BM
Monday June 6th: Poster Presentation Abstract #6571
"Interim PK analysis results of a phase IIa, open-label, randomized, pharmacokinetic comparative, cross-over study of melphalan HCl for injection (propylene glycol-free) and alkeran for injection for myeloablative conditioning in multiple myeloma patients undergoing autologous transplantation."
Omar S. Aljitawi, MD
Background: High dose melphalan and autologous transplantation is a standard procedure in transplant eligible multiple myeloma patients. The marketed formulation of melphalan, Alkeran, has marginal solubility and limited chemical stability upon reconstitution. Alkeran uses propylene glycol as a co-solvent, which has been reported to cause some complications. On the other hand, Melphalan HCl for Injection (Propylene Glycol-Free), is a reformulation of Alkeran for Injection developed by CyDex Pharmaceuticals, Inc.. It incorporates the Captisol brand of SBECD as a co-solvent which improves stability, potentially allowing for alternative dosing such as longer infusion times.
Methods: This is a planned interim pharmacokinetic (PK) analysis of a phase IIa, open-label, randomized, cross-over design study. In this study,the PK of Melphalan HCl for Injection and Alkeran for Injection are assessed in the same MM patients undergoing transplantation. This analysis was planned after 15 patients were treated on the study. The PK measures were determined using WinNorLin 6.1, and a paired difference t-test was used to determine statistical signficance. Furthermore, the safety and tolerability of high-dose melphalan HCL and rates of myeloablation and subsequent engraftment are determined in all patients.
Results: All patients achieved myeloablation followed by successful engraftment. Median time to myeloablation was 6.5 days (range 4-7 days). Median time to neutrophil engraftment was day +10. Beside expected grade 2-3 toxicities related to high dose melphalan, no additional toxicities were reported. PK analysis revelaed that Cmax, and AUC were statistically significantly higher after PG-free Melphalan HCL infusion.
Conclusions: Melphalan HCl for Injection, administered as half of a high-dose conditioning regimen, appears to result in statistically significant greater exposure to drug and successful myeloablation and subsequent engraftment with no additional toxicity.