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.