- Sorry these notes are a bit delayed, this event got buried in the midst of the ASCO abstract release.
- Here are my brief notes from a 15 min 5/17/2011 SUPG webcast at noble financial conference:
- different speaker today - Michael V. McCullar, Ph.D., senior vice president, strategy and discovery operations...not too comfortable speaking and less effective...but read same slides as always
- Amuvatinib aka mp470 p2 trial will begin "shortly"
- Confirmed that Dacogen elderly AML US sNDA has been submitted by Eisai
- expect european submission later this year
SUPG and its Dacogen partner GSK will present the following abstracts at the ASCO meeting June 4-7, 2011:
--Abstract 5011 describes a phase 2 study of Dacogen (decitabine) plus carboplatin in ovarian cancer. Of 17 pts enrolled, 9 were progression free at 6 months. There was 1 CR, 5 RECIST PRs, 6 SD. The dacogen combo treatment restored tumor sensitivity to platinum-based chemotherapy and looks quite encouraging.
--Abstract 8530 describes a phase 1/2 combo study of Dacogen and temozolomide in metastatic melanoma. The phase 2 portion represented 33 evaluable pts (42% with brain metastases) and yielded 1 CR, 4PR, and 13 pts with SD. Median PFS was 2.8m, median OS was 15.2m (compare to historical data of 7.7m), and 1 yr survival was 62% (compare to 25%). As with the above study, data are encouraging enough to support a randomized trial.
--Abstract 6504 is the much-awaited phase 3 data in elderly AML for Dacogen vs physician's choice of supportive care/araC chemotherapy. The analysis at 396 death events (82% of pts) showed an OS of 7.7m for dacogen vs 5.0m for comparator arm (HR 0.85, p=0.10). At 446 events, OS valued were the same, with a slight improvement in HR to 0.82. The secondary endpoint of complete responses (CR) plus CR with incomplete platelet recovery (CRp) was 18% for dacogen vs 8% (p<0.001). The question now of course is will the FDA and/or EMEA approve dacogen for these patients despite the miss on the primary endpoint. I think most of us would agree that pts would benefit, but that isn't always a good enough rationale.
--Abstract 6537 summarizes a phase 2 trial in which pts received G-CSF to shift cancer cells to S phase before treatment with Dacogen and cytarabine. 9 pts with AML or MDS were enrolled. 1 CR and 1 PR were observed. Median OS was 30 days- this priming technique did not improve OS over current standard of care in this small pilot in this population.
--Abstract 3074 summarizes the final phase 1b data for Amuvatinib (MP-470), given orally, in combinations with 5 difference standard of care (SOC) regimens in various advanced cancers. 100 pts were enrolled and no amuvatinib specific dose limiting toxicities were observed (MTD not reached), and 12 PRs and 44 SD were achieved. 11/12 PRs were observed in combo with either paclitaxel/carboplatin or carboplatin/etoposide. 5 of 11 pts with SCLC or neuroendocrine tumors had PRs- the basis for the proposed p2 study in SCLC that was originally supposed to initiate in the 2h2010, but has yet to start.
Saturday June 4th: Oral Presentation 5:30 PM - 5:45 PM Abstract #5011
"A phase II study of decitabine and carboplatin in recurrent platinum (Pt)-resistant ovarian cancer (OC)."
Daniela Matei, MD
Background: Aberrant DNA methylation is a hallmark of cancer. Preclinical studies showed that hypomethylating agents reverse Pt resistance, supporting testing low dose decitabine (D) combined with carboplatin (Cp), in recurrent Pt-resistant OC.
Methods: Key eligibility included recurrent OC, Pt-resistant or Pt-refractory, measurable (RECIST) or detectable (GCIC), normal organ function, no limit on prior therapy. Treatment was D 10mg/m2 d1-5 prior to Cb (AUC 5, d8), based on phase I results. Primary endpoint was response rate (RR). Secondary endpoints were clinical benefit rate (CBR), progression free survival (PFS), safety, and overall survival (OS). PBMCs, plasma, and tumor biopsies were collected on d1 and d8 for assessment of biomarkers correlating with PFS. Genome-wide DNA methylation and gene expression profiling of tumors used Infinium and Affymetrix U133A arrays. Global (LINE-1) and gene-specific DNA methylation and expression levels were measured by pyrosequencing and qRT-PCR. Data analysis included linear mixed-effects models, statistical analysis for microarrays (SAM), clustering, functional pathway prediction, and gene ontology.
Results: 17 patients were enrolled. Median age was 60 (45-83), median number of prior regimens was 5 (1-10). 15 patients had Pt-resistant and 2 Pt-refractory OC; 16 had measurable, 1, detectable OC. 1CR (GCIC) and 5 PRs (RECIST) were observed (RR=35%, 95% CI: 14%-62%). 6 other patients had stable disease. CBR was 70% and median PFS was 309 days. 9 patients (53%) were free of progression at 6 mos. Most common grade 3-4 AEs were neutropenia (23%), thrombocytopenia, leukopenia, anemia (11% each). LINE-1 methylation was decreased on d8 vs. d1 in PBMC DNA (P<0.05). Demethylation of OC-associated genes MLH1, RASSF1a, HOXA10, and HOXA11, in tumors from d1 to d8 is positively correlated with PFS (P<0.05). Inflammatory response genes were altered in tumors on d8 vs. d1, and expression of pathways involved in proliferation, transformation, survival, and DNA repair were reduced on d1, correlating with PFS (P<0.01).
Conclusions: Low-dose D alters DNA methylation restoring sensitivity to Cp in patients with heavily pre-treated OC, resulting in a high RR and prolonged PFS
Monday June 6th: Poster Presentation Abstract #8530
"Final results of phase I/II study of decitabine (DAC) combined with temozolomide (TMZ) in metastatic melanoma (MM)."
Jan H. Beumer, PhD, PharmD
Background: TMZ is widely used in MM despite low response rates (7-13%) and no improvement in median overall survival (OS) 7.7 months (m) when compared to dacarbazine in Phase III trials. The DNA repair protein, O6-methylguanine-DNA-methyltransferase (MGMT), is implicated in melanoma resistance to TMZ and can be depleted with extended schedule TMZ. DNA mismatch repair (MMR) deficiency is another mechanism of resistance that can be reversed with DNA hypomethylators such as DAC. We sought to determine the recommended phase II Dose (RP2D), safety, and efficacy of DAC in combination with extended schedule TMZ in MM. Methods: In the Phase I portion, pts were treated with 2 dose levels (DL) of DAC: 0.075 mg/kg IV QD and 0.15 mg/kg IV QD. DAC was administered qd x 5 d/wk for 2 wks, and TMZ was administered PO at 75 mg/m2 qd for 4 wks, starting on wk 2 of each 6-wk cycle. A Simon 2-stage Phase II design with success defined as ≥5 Objective Responses (OR) in 34 evaluable patients gave µ=0.10 and 85% power. PK sampling was performed on Days 1 and 8; PBMC and tumor tissues were studied on Days 1, 8, 15 and 29 of cycle 1.
Results: The RP2D is DAC 0.15 mg/kg and TMZ 75 mg/m2. 35 patients were accrued to the Phase II portion of the study, the majority with M1c disease (88%); brain metastases were present in 42%. 2/35 were not evaluable (NE) for efficacy. For the remaining 33 patients, the best RECIST responses were 1CR, 4 PR, 13 SD, and 15 PD, for an OR rate of 15% and a clinical benefit rate (CR+PR+SD) of 54%. The median PFS was 2.8 m, median OS was 15.2 m (compared to 7.7 m), and 1-year OS rate was 62% (compared to 25%). Grade 3/4 neutropenia was observed in 68% of pts but reversible, lasting >7 d in only 5 pts (DLT rate 15%). Only 2 patients discontinued therapy for hematologic toxicity. PK studies revealed no effect of DAC on the PK profile of TMZ.
Conclusions: The combination of DAC and TMZ is safe and results in improved median OS from historic reference of 7.7 m to 15.2 m, and 1-year OS rate from 25% to 62%. The addition of DAC appears to improve the clinical activity of TMZ, possibly through dual modulation of DNA repair (depletion of MGMT and re-expression of MMR), and warrants further evaluation in a randomized setting
Monday June 6th: Oral Presentation 10:45 AM - 11:00 AM Abstract #6504
"Results from a randomized phase III trial of decitabine versus supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed AML."
Xavier G. Thomas, MD, PhD
Background: We conducted a Phase 3 trial, the largest to date in older patients with acute myeloid leukemia (AML), comparing decitabine (DAC) to patient's choice with physician's advice (treatment choice – TC) of supportive care (SC) or low-dose cytarabine (AraC).
Methods: In this open-label Phase 3 trial, newly diagnosed patients ≥65 years of age with de novo or secondary AML and poor- or intermediate-risk cytogenetics were randomized to two treatment groups: TC: either SC or 20 mg/m2 AraC subcutaneously once daily for 10 consecutive days, every 4 weeks; or DAC 20 mg/m2 as a 1-hour IV infusion once daily for 5 consecutive days, every 4 weeks. The primary endpoint was overall survival (OS).
Results: Of 485 enrolled patients, 242 were randomized to DAC and 243 to TC. DAC patients had a median duration of treatment of 4.4 months versus 2.4 months for those on the TC arm. The protocol-specified final analysis with 396 (81.6%) deaths showed a statistically non-significant but favorable trend for increased OS for patients treated with DAC, with a median survival of 7.7 months (95% CI: 6.2, 9.2) versus 5.0 months (95% CI: 4.3, 6.3) in the TC arm. The HR was 0.85 (95% CI: 0.69, 1.04), and p=0.10. An updated unplanned OS analysis with 446 (92%) deaths showed the same median survival with strengthened evidence of the DAC effect (HR 0.82; 95% CI: 0.68, 0.99; nominal p=0.03). The secondary endpoint of CR+CRp rate was 18% (DAC) versus 8% (TC) with OR=2.5 (95% CI: 1.4, 4.8) and p=0.001. AE rates were consistent with the known DAC safety profile and without major differences between the treatment arms. The most frequently reported Grade 3 or 4 hematologic AEs were thrombocytopenia, anemia, neutropenia, and febrile neutropenia.
Conclusions: Compared with the accepted standard therapies used in this study to treat older patients with AML, DAC showed an overall survival advantage and higher response rates without major differences in safety.
Monday June 6th: Poster Presentation. Abstract #6537
"A phase II study with decitabine, low-dose cytarabine and G-CSF priming in high-risk myelodysplastic syndromes, refractory/relapsed acute myelogenous leukemia or acute myeloid leukemia in patients with significant comorbidities."
James Butera, MD
Background: The incidence of AML increases with advancing age; the median age of presentation for AML is 69 years. At present, there are limited treatment options available for elderly patients with AML or those with refractory disease. Both cytarabine and decitabine exert their cytotoxic effect on leukemic cells in the S phase. G-CSF priming has the ability to move leukemic cells into S phase.
Methods: We evaluated the use of low-dose cytarabine 20 mg/m2 SC, decitabine 20 mg/m2 IV and G-CSF 5 mcg/kg days 1-5 every 4 weeks in patients with high risk MDS or refractory/relapsed AML or elderly AML patients with significant co-morbidities. Between 04/2009 and 02/2010, 9 of a planned 12 patients were enrolled in the trial. 5 patients had AML, 4 had high-risk MDS. Median age was 72 years (range 60-89). ECOG performance status was 0-1. 1 AML patient had failed allogeneic hematopoietic stem cell transplantation, and 1 patient had relapsed after induction with multiple chloromas. All high-risk MDS patients were previously only treated with supportive care.
Results: 1 of 5 patients with AML had complete remission (CR), 2 had progressive disease, and 2 were not evaluable. The only patient with CR was a newly diagnosed AML M5 elderly patient. 1 of 4 patients with high-risk had partial clinical response defined by significant hematologic improvement in 2 cell lines. Median number of cycles given was 2 (range 1-6). The median overall survival was 30 days (range: 14-234 days). Grade 3-4 toxicities included: mucositis (n=1), pulmonary infiltrates/infection (n=2), ANC decrease (n=5), thrombocytopenia (n=6), anemia (n=6).
Conclusions: Although this is a small pilot study, the combination of decitabine, low-dose cytarabine with G-CSF priming does not demonstrate improvement over the current standard of care for this high-risk, refractory patient population.
Monday June 6th: Poster Presentation. Abstract #3074
"Amuvatinib (MP-470), an oral dual inhibitor of mutant kinases and DNA repair: Final results from a 100-patient, 5-arm phase Ib trial in combination with five standard of care (SOC) anticancer regimens."
Kamalesh K. Sankhala, MD, MBBS
Background: Amuvatinib is an oral multi-targeted TKI which inhibits the mutant forms of c-kit, and PDGFR±. It also disrupts DNA repair probably through suppression of Homologous Recombination protein Rad51.
Methods: Adults with cancer diagnosis appropriate for one of the 5 SOC regimens to be studied received amuvatinib (dry-powder capsules) in combination with SOC. The 5 SOC regimens were: paclitaxel/carboplatin (PC), carboplatin/etoposide (CE), topotecan (T), docetaxel (D), and erlotinib (E). Amuvatinib doses were escalated until the MTD of the drug in combination with SOC agents was reached. The primary objectives of the study were to determine the MTD, DLTs, and quantify the effects of amuvatinib on the PK of SOC agents. Other objectives included pharmacodynamic parameters and tumor response.
Results: 100 patients, mean age of 58 (range, 25 84) years were enrolled. M/F:35/65. ECOG PS 0/1/2:15/78/7, respectively. 90% of patients had prior cancer treatment. Patients were treated with amuvatinib plus: PC (23 patients); CE (22); T (20); D (15), and E (20). Amuvatinib doses were escalated from 100 mg PO QD to 400 mg PO BID on a continuous basis. Amuvatinib did not alter the PK of SOC agents, except D. The MTD was not reached and amuvatinib-related DLTs were not identified in this study. Most common ("e 15% of patients) adverse events (AEs) related to treatment were expected AEs of SOC: neutropenia, fatigue, alopecia, diarrhea, thrombocytopenia, and anemia. Overall, 12 PRs and 44 SDs by RECIST criteria were observed for an overall disease control rate of 56% (95% CI, 46 66). The PC and CE combination arms with amuvatinib showed the most activity with 6 and 5 PRs, respectively. Small Cell Lung Cancer (SCLC) and Neuroendocrine (NE) tumors were the most sensitive with 5 of 11 SCLC or NE patients achieving PR. Rad51 modulation and increased DNA damage (53BP1 foci) was observed in skin punch biopsies.
Conclusions: Amuvatinib is well tolerated in combination with 5 SOC regimens. Several PRs were observed. The results support further investigation of amuvatinib in combination with CE or PC in SCLC and NE tumors.
Synta Pharma $SNTA will present the following abstracts on their HSP90 inhibitor ganetespib at ASCO June 4-7, 2011.
Abstract 7500 presents the openlabel phase 2 trial of ganetespib in advanced NSCLC. Unfortunately the data contained in the abstract are less current than what was presented in February 2011 (see summary on SNTA research page). Hopefully the data will be updated at the meeting.
Abstract e13591 summarizes preliminary phase 1 combo data of docetaxel plus gantespib that is the basis for the p2b/3 program initiating this quarter. 4 of the first 7 evaluable pts had stable disease (SD) after 2 cycles. Hopefully the data will be updated at the meeting.
Abstract 10011 summaries an open-label phase 2 trial of ganetespib in advanced GIST pts. 12/23 pts had SD, far exceeding the efficacy hurdle to expand the study. However there was concern that the dosing schedule might not be optimal for reducing tumor levels of mutant KIT protein.
Abstract 3051 updates the ongoing phase 1 trial of twice-weekly ganetespib in advanced solid tumors. 49 pts are reported, currently expanding 144 mg/m2 dose cohort due to DLT of liver enzyme elevation. Half-life 10-14 hrs. Durable PR (melanoma) and 2 durable SD (NSCLC) seen so far.
Saturday June 4th: Oral Presentation 8:00 AM - 8:15 AM Abstract #7500
"An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC)."
Kwok-Kin Wong, MD
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. Ganetespib has been well tolerated and has shown promising antitumor activity in early trials in multiple cancers.
Methods: Patients (pts) with advanced NSCLC who failed prior treatments received 200 mg/m2 ganetespib as a 1-hr infusion once weekly for 3 of a 4-wk cycle in a Simon two-stage study design assessing primary endpoint of PFS rate at 16 wks. Initial cohorts were defined by mutation status: A) EGFR B) KRAS C) EGFR and KRAS wild type (WT). If ≥2/14 pts in A, B or C were progression-free at 16 wks, enrollment increased to 23 pts for that cohort. Tumor response was assessed every 8 wks. Cohort D was added to include 35 additional EGFR and KRAS WT pts with adenocarcinoma histology. Additional mutational analysis of BRAF, PIK3CA, ERBB2 and MET, as well as FISH analysis for ALK translocation, were performed for Cohorts C and D.
Results: 73 pts (31 M, 42 F; median age 62 yrs, range 28-82; ECOG 0-1; prior therapies range 1-10) received a median of 2 cycles (range 1-12) of ganetespib in cohorts A (14), B (17), and C+D (42). AEs reported in ≥20% of pts included diarrhea, fatigue, nausea, anorexia, constipation, and dyspnea and were generally grade 1-2. Expansion criteria were achieved for cohort C, including a durable partial response (PR) and seven pts with prolonged stable disease (≥16 wks). Cohort D continues recruitment. Mutational analyses of Cohort C and D samples will be presented.
Conclusions: Ganetespib administered as a single-agent is well-tolerated in pts with NSCLC at 200 mg/m2 once weekly without severe liver, ocular, cardiovascular or renal toxicity. Clinical activity has been observed in pts with advanced NSCLC tumors harboring wild-type EGFR and KRAS.
Abstract # e13591 (Publication-only abstract)
A Phase 1 and Pharmacokinetic Study of Ganetespib (STA-9090), a Heat Shock Protein 90 Inhibitor, in Combination with Docetaxel in Subjects with Advanced Solid Tumor Malignancies.
R. Donald Harvey et al
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally
unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown
superior activity to these agents in preclinical studies. Ganetespib has been well tolerated
and has shown promising antitumor activity in early trials in multiple cancers. Based on
preclinical synergy between ganetespib (G) and docetaxel (D), a phase I pharmacokinetic
(PK) and feasibility study was initiated with the combination.
Methods: Patients with advanced solid tumor malignancies, ECOG performance status
(PS) 0-2 and adequate liver, renal and bone marrow function were eligible. Sequential
cohorts of patients are treated with increasing doses of D (day 1) and G (IV weekly, days
1, 8). PK sampling was performed on days 1 and 8 of cycle 1. Treatment cycles were
repeated every 3 weeks. A standard 3+3 dose escalation scheme was utilized. The
primary endpoint was determination of optimal doses of the two agents for combination
Results: Twelve patients have been enrolled. Median age-63 (44-72); 1-M, 11-F; ECOG
PS 0-1; # of prior regimens: 1 (2 pts), 2-3 (5 pts), >3 (5 pts). At dose levels 1 (D-60
mg/m2, G-150 mg/m2) and 2 (D-75 mg/m2, G-150 mg/m2), none of 6 patients initially
treated had a DLT. Two of 4 patients at dose level 3 (D-75 mg/m2, G-200 mg/m2) had
DLTs (g4 febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of
dose level 2. Common adverse events included neutropenia (n=9), diarrhea (n=4),
fatigue, vomiting, and nausea (n=3 each). Grade 3/4 toxicities included neutropenia (n=9)
asthenia, febrile neutropenia and pulmonary embolus (n=1 each). The median number of
cycles is 2 (1-6), with 6 patients still on study. Among 7 patients evaluable for response,
4 had disease stabilization following cycle 2, with one > 12 weeks. PK data will also be
Conclusions: The combination of docetaxel and ganetespib is well tolerated at the
recommended doses of 75 mg/m2 and 150 mg/m2, respectively. Promising anti-cancer
activity was noted, and a randomized phase II study of the combination will soon be
initiated in advanced NSCLC.
Saturday June 4th: Poster Presentation Abstract #10011
"An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST."
George D. Demetri, MD
Background: Ganetespib, a potent, synthetic small-molecule inhibitor of Hsp90, has shown an improved safety profile relative to 1st-generation agents as well as promising signals of antitumor activity in early clinical studies, including one pt with PDGFRAD842V mutant GIST. Preclinical studies have shown that human GIST cells with primary or secondary TKI-resistance mutations are highly sensitive to ganetespib, justifying this phase 2 trial in GIST.
Methods: Pts with advanced GIST following failure of prior therapy (tx) received ganetespib (200 mg/m2) as a 1 hour IV infusion qw for 3 wks of a 28 day cycle. GIST status was assessed q8 wks per RECIST, until progression. In this Simon’s 2 stage study design, if ≥4/23 pts in Stage 1 had clinical benefit (CR+PR+SD ≥ 16 wks) enrolment would continue with Stage 2. Hsp90 client protein levels were analyzed in biopsies pre-tx and 24-48 h post-ganetespib in a subset of pts.
Results: 26 pts (15 M, 11 F; median age 53 yrs, range 33-67; ECOG status 0-1; median 5 prior tx regimens, range 3-12, wild-type PDGFRA) received a median of 2 cycles of ganetespib (range 1-8). AEs reported in >20% of pts were generally NCI CTC grade 1-2 and included diarrhea, fatigue, nausea, vomiting, increased alkaline phosphatase, headache, insomnia, and abdominal pain. 12/23 evaluable pts had SD (4 SD ≥16 wks, 8 SD ≥8 wks), meeting formal criteria to enroll Stage 2. However, analysis of client proteins in paired tumor biopsies from 4 pts did not show prolonged inhibition of activated KIT or its downstream pathways. These data suggest the once-weekly tx schedule is likely not optimal for inhibition of KIT. At this time, accrual has been limited to pts with PDGFRA mutations to allow further preclinical development of alternative schedules and combinations.
Conclusions: Ganetespib given by once-weekly dosing was well tolerated in pts with heavily pre-treated advanced GIST, with no evidence of severe liver, ocular, cardiac or renal toxicity. Disease stabilization was seen in a subset of pts. Advanced preclinical modeling is ongoing to optimize the impact of ganetespib on mutant KIT in GIST.
Monday June 6th: Poster Presentation Abstract #3051
"A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: Updated report."
Daniel C. Cho, MD
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. It has been well tolerated and shown promising antitumor activity in early trials in multiple cancers. Preclinical data indicate that different client proteins show disparate expression kinetics upon Hsp90 inhibition. Therefore, twice-weekly dosing may be needed in some tumor types.
Methods: Patients (pts) with solid tumors who have exhausted standard treatment options received ganetespib as a 1 hr infusion twice weekly for 3 weeks (wks) of a 28 day cycle until disease progression. Serial PK and pharmacodynamic samples were obtained during cycle 1. Safety assessments included frequency and grade of AEs, laboratory parameters and ECG changes.
Results: Data are presented for 49 pts (22 M, 27 F; median age 55 yrs, range 32-81; ECOG status range 0-2) treated at doses from 2-144 mg/m2. Pts received a median of 2 (range 1-12) cycles of ganetespib. AEs reported in ≥20% of pts treated at doses from 2-120 mg/m2 are fatigue, diarrhea, nausea, anemia, abdominal pain, constipation, anorexia, vomiting, and headache; the majority of events were mild to moderate in severity with absence of severe liver, ocular, cardiac and renal toxicity. Two DLTs (elevated transaminases) have been reported in the 10 and 144 mg/m2 cohorts; expansion of the latter cohort is ongoing. Ganetespib shows linear PK, rapid distribution, a mean terminal half-life of 10-14 hours, a volume of distribution greater than total body water and no accumulation in plasma. HSP70 plasma protein levels will be presented. A confirmed durable PR by RECIST has been seen in a pt with metastatic melanoma. Additionally, 2 NSCLC pts who received 6 months of treatment had durable SD, with tumor shrinkage.
Conclusions: Ganetespib has been well tolerated at dose levels up to 120 mg/m2 administered twice weekly. Preliminary safety profile, activity signals and differences in client protein kinetics warrant continued evaluation of ganetespib using a twice-weekly dosing regimen. Dose escalation continues
MYRX will present the following abstracts at ASCO June 4th, 2011:
Abstract 2088 describes the results from the second cohort of a single-agent Azixa phase 2 study in recurrent gliobastoma (GBM). Results from patients who had previously failed Avastin (bevacizumab) have been previously disclosed and are summarized on the MYRX research page. In this group, 31 pts completed a median of 2 cycles of Azixa therapy, which was well tolerated. 14% of pts were progression free at 6 months, with median PFS of 1.8 months and median OS of 9.9 months. 3 PR's and 7 SD's (median 3.9 months) were observed for a clinical benefit rate of 32%- described as "modest activity". These data are all better than seen in Avastin-experienced patients.
Abstract 10529 shows preclinical xenograft data demonstrating the activity of cancer metabolism inhibitor MPC-9528 in several different dosing schemes.
Saturday June 4th Poster Presentation Abstract #2088
"Phase II study of verubulin (MPC-6827) for the treatment of subjects with recurrent glioblastoma naïve to treatment with bevacizumab."
Lyndon J. Kim, MD
Background: Treatment options are limited for recurrent glioblastoma (GBM). Verubulin is a microtubule destabilizer and vascular disrupting agent that achieves high brain concentration relative to plasma in animals.
Methods: Adults with recurrent GBM who failed prior standard therapy were eligible. The primary endpoint was 6 -month progression-free survival (PFS -6). Eligible subjects had a KPS "e 60, were free of active cardiovascular disease and uncontrolled hypertension and had no prior treatment with angiogenic inhibitors. Verubulin was administered at 3.3mg/m2 as a 2-hour IV infusion once weekly for 3 consecutive weeks in a 4-week cycle. Response was assessed using the Macdonald criteria. The planned sample size was thirty-four subjects.
Results: 31 adults were treated (20 men; 11 women). All subjects had prior tumor resection, a median of two chemotherapies (up-front with RT and salvage); the majority were in first relapse (77%). Median age and KPS were 56 years (range 23 -74) and 90 (range 70 -100), respectively. Median number of verubulin cycles completed was 2 (range 0 -12); one subject remains on treatment. The most common adverse events were fatigue (19%), nausea (10%) and constipation (6%). One subject discontinued the study due to a grade 2 ventricular arrhythmia. Another subject with significant cardiovascular risk factors had a non-fatal myocardial infarction. 3 subjects (10%) did not complete at least 2 cycles of treatment and were not evaluated for disease response. The PFS-6 was 14% (4/28) [90% CI: 3%, 25%] with a median PFS time of 1.8 months [90%CI: 1.8, 1.9], a mean PFS time of 2.6 months [range 0.8 -11.9], a median overall survival of 9.9 months [90%CI: 8.3, 11.6] and a mean overall survival of 6.7 months [range 1.1 -15.9]. Best overall response by Macdonald criteria was partial response (n=3; 10%) and stable disease (n=7; 23%). Median duration of stable disease was 3.9 months [90% CI: 3.8, 4.0].
Conclusions: Single agent verubulin, in this dose and schedule, in adults with recurrent GBM is well tolerated and associated with acceptable toxicity, and appears to have modest activity.
Saturday June 4th. Poster Presentation Abstract 10529
"Activity of the cancer metabolism inhibitor MPC-9528 in xenograft models: Comparison of different dosing schedules."
Baichwal et al.
Background: MPC‑9528 is a potent, selective, orally bioavailable inhibitor of nicotinamide phosphoribosyltransferase (Nampt) that catalyzes the rate-limiting step in NAD biosynthesis from nicotinamide. Nampt inhibition results in NAD depletion, inhibition of ATP synthesis and cell death. MPC-9528 has potent tumoricidal activity against cancer cell lines of diverse origin and induces regressions in xenograft models. Here we explore determinants of MPC-9528 activity in xenografts by comparing tumor NAD depletion and survival with alternate dosing schedules. Methods: HT1080 human fibrosarcoma cells were implanted subcutaneously into athymic mice (nu/nu) for xenograft studies. MPC-9528 was dosed orally, once weekly or once or twice daily, for two or three weeks. NAD concentration in xenografts and mouse organs was determined by LC-MS/MS.
Results: MPC-9528 (75 mg/kg) dosed weekly for three weeks resulted in 75% xenograft regression 8 days after the last dose. ED50 with this schedule was 44 mg/kg and doses at or below 35 mg/kg showed no activity. All doses were well-tolerated with <10% change in median body weight. A dose of 10 mg/kg once daily, 3 mg/kg twice daily or 4 mg/kg twice daily for 14 days resulted in 91%, 92% and 100% tumor regression, respectively, by the end of dosing. Two of 10 animals in the 10 mg/kg and 3 mg/kg groups, and 9 in the 4 mg/kg group had no detectable tumors at the end of dosing. In the 10, 3 and 4 mg/kg groups, 40%, 50% and 70% of the mice, respectively, were tumor free thirty-four days after the last dose. Pharmacokinetic profiles of a 3, 10 or 75 mg/kg dose of MPC-9528 indicated that anti-tumor activity was not dependent on maximal plasma concentration or total absorbed dose but on maintenance of compound concentration above a specific efficacious concentration threshold. MPC-9528 also caused a rapid and sustained reduction of NAD in tumors with the magnitude and kinetics of NAD change dependent on the dose and schedule.
Conclusions: MPC-9528 induces regression of xenografts when its plasma concentration is maintained above a threshold efficacious concentration. It shows comparable activity when given intermittently, once weekly, or continuously on a once or twice daily schedule.
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