A phase 1b/pharmacokinetic trial of PTC299, a novel post-transcriptional VEGF inhibitor, for AIDS-related Kaposi’s sarcoma: AIDS Malignancy Consortium trial 059

Vascular endothelial growth factor (VEGF) plays an important role in Kaposi’s sarcoma (KS). We administered PTC299, a post-transcriptional inhibitor of pathogenic VEGF, to persons with HIV-related KS. Seventeen participants received three different doses of PTC299. Adverse events typically observed with VEGF-inhibition were absent. Three participants had partial tumor responses and 11 had stable disease. There were no differences in exposure to PTC299 by antiretroviral regimen. Serum VEGF, but not KSHV DNA, decreased on treatment. Given redundancies in the VEGF feedback loop, future trials should consider combining PTC299 with agents that inhibit different pathways implicated in KS and KSHV proliferation

Genomic Complexity in Diffuse Large B-Cell Lymphoma Is Associated with p53 Expression and Inferior Survival

Abstract Genomic complexity in diffuse large-B-cell lymphoma has recently been reported to have strong prognostic value in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-based immunochemotherapy (PMID:22975378). In that study, the presence of the respective gain/loss of at least one of nine genomic markers along the CDKN2A-TP53-RB-E2F axis was used to define cases with “complex” genomes. Genomic imbalance at these specific loci were suggested to functionally contribute toward cell cycle deregulation resulting in increased overall genomic instability. Other clinicopathologic studies have clearly demonstrated that inferior survival is also associated with elevated expression of p53, which serves as a surrogate for TP53 mutation. To date, there have been very few studies, if any, that have examined the relationship between genomic imbalance and complexity, and clinicopathologic features in DLBCL, in particular with relevance to TP53. To this end, DNA was extracted from either sections of formalin-fixed paraffin-embedded biopsies with greater than 70% tumor burden or tumor-enriched cores of 85 DLBCL specimens from patients treated at a single institution (with IRB approval). DNAs from 39 specimens have been blindly submitted to array-CGH to date, using a targeted array (Agilent Technologies). The design permitted assessment at 50 loci commonly gained/lost in DLBCL (arising within 36 minimal common regions [MCRs]) using well defined scoring criteria. Specimens were classified as “complex” if any one of the following aberrations were detected: gain of 1q23, 6p21, 7q22, 12q15, or 19p13, or loss of 9p21, 13q14, 16q12, or 17p13. For all cases, expression of p53, MYC, BCL2, Ki-67, and Epstein-Barr virus (EBV) had previously been examined and reported (PMID:24619762) as was the COO subtype. Correlative analyses with overall survival (OS) were tested using the Kaplan Meier method and log rank statistic. Significance of pathogenomic correlations were examined using the Fisher’s exact t-test (P&lt;0.05 was considered significant). Of the 39 cases evaluated to date, IPI was available for 34. For the preliminary analysis comprising 39 cases, genomic complexity (observed for 22 cases) did not significantly correlate with IPI, consistent with the prior report where genomic complexity associated with inferior survival independent of IPI (PMID:22975378). However, genomic complexity did portend shortened survival within the preliminary 39 patients studied to date (P&lt;0.01) and a trend was observed for the 29 who received RCHOP or RCHOP-like therapy (P=0.05) (for the remaining 10 cases, treatment status was unknown for 7 and 3 received palliative care). Genomic complexity based on absolute number of aberrations for the entire 50 assessed (&gt;1), did not exhibit significant association with outcome. Fourteen of 18 cases with p53 expression (&gt;30%) had complex genomes, which was significantly enriched compared with cases with low or no p53 expression (P &lt;0.03). No significant correlation was found between genomic complexity and BCL2 (&gt;70%) and MYC (45%) expression, nor with COO subtype. Specifically for TP53, loss of 17p13 was detected in 7/39 cases, and positively correlated with adverse outcome both for the entire dataset (P=0.05) and for RCHOP-treated patients (P=0.02). Interestingly, of those with loss, 3 were not positive for p53 expression and overall, p53 expression did not correlate with 17p loss. Previous analyses in this dataset had also revealed that co-expression of p53 and MYC, but not BCL2 had an enhanced negative effect on outcome. Only one of 5 cases with co-expression of p53 and MYC also displayed 17p loss. Overall then, p53 expression was associated with underlying genomic complexity but specific loss of the TP53 locus appeared to mark another smaller subset of DLBCL patients with inferior survival, independent of p53 expression. Expansion of the study to include the additional 46 cases is currently ongoing to confirm these emerging correlative patterns, as is determination of the TP53 mutation status of each specimen. Additional correlative pathogenomic studies will also be afforded with the larger dataset, examining the role of the 8 other loci of genomic gain/loss suggested to underlie genomic complexity in DLBCL. Disclosures Ma: Cancer Genetics, Inc.: Employment, Stock option holder Other. Houldsworth:Cancer Genetics, Inc: Employment, Stock and stock option holder Other. </jats:sec

Phase I Study of Noscapine for Patients with Non-Hodgkin’s Lymphoma or Chronic Lymphocytic Leukemia Refractory to Chemotherapy.

Abstract Noscapine is an alkaloid derived from opium, which lacks sedative, euphoric, analgesic or respiratory depressant properties. Antitumor activity of Noscapine has been demonstrated both in vivo, against human lymphoid tumor cells, and in vitro, in human tumors implanted in athymic mice. Noscapine induces conformational changes in tubulin, which results in altered microtubule assembly. In this Phase I trial, cohorts of subjects with relapsed/refractory non-Hodgkin’s lymphoma (NHL) or chronic lymphocytic leukemia (CLL/SLL) were treated at three different dose levels of total daily doses of 1 g, 2 g, and 3 g. At each dose level the drug was administered orally on a three times a day schedule. The total duration of treatment was 49 days. Results: Twelve subjects with a median age of 65 years (range 38–71) have been accrued. Four subjects had CLL/SLL, 2 had mantle cell lymphoma, one had follicular grade III, 4 had DLC, and one had lymphoplasmacytic low grade lymphoma. 10 subjects are evaluable for response. Partial response was seen in 1 subject with follicular grade III disease. The duration of this PR is 56+ months. Stable disease was seen in a case of mantle cell lymphoma (duration 30 days) and a case of DLC (duration 77 days). The remaining 7 subjects had progression of disease. Noscapine has been well tolerated, with no grade 3 or 4 hematological toxicities. One grade 3 neurotoxicity consisting of depressed level of consciousness was experienced at the 3 g dose level. We conclude that a larger study of Noscapine is warranted to evaluate the efficacy of the compound in patients with lymphoma. The oral formulation, suggestion of efficacy and relative lack of toxicity make Noscapine an attractive candidate for further study.</jats:p

Rituximab Plus CHOP Given Every 15 Days with GM-CSF (sargramostim) In Patients Withnewly Diagnosed Diffuse Large B-Cell Lymphoma

Abstract Abstract 4886 Background: The R-CHOP regimen administered every three weeks has become the standard of care for treatment of patients with diffuse large B-cell lymphomas. Previous studies have not shown an advantage of dose dense (cycles given every 2 weeks) R-CHOP therapy. Granulocyte-macrophage colony stimulating factor (GM-CSF), in addition to stimulating hematopoetic recovery augments dendritic cell numbers and promotes antigen presentation, induces immune recognition of tumor cells, causes antibody dependent cytotoxicity, and upregulates activity of rituximab. In a Phase II study, we analyze the efficacy and tolerability of R-CHOP given every 15 days with GM-CSF administered on days 3 through 13 of each cycle. Methods: All patients were treated with Rituximab, 375 mg/m2; Cyclophosphamide, 750 mg/m2; Doxorubicin, 50 mg/m2; Vincristine, 1.4 mg/m2, all given IV on day 1; oral prednisone 100 mg given orally on days 1–5 and subcutaneous GM-CSF, 250 mg/m2 on days 3–13. Chemotherapy cycles were repeated every 15 days. Results: In this mid-study evaluation, thus far 36 patients with a median age of 53 (range 22–81) have been accrued. All patients were previously untreated and had CD20+ diffuse large B cell lymphoma. 26 (72%) patients had stage III (8) or IV (18) disease. Thirteen (36%) patients had bone marrow involvement. Twenty eight (77%) had elevated serum LDH levels, and 16 (44%) patients had an intermediate or high risk IPI score. Toxicities have been primarily hematologic with transient grade 3 or 4 neutropenia in 27 (74%) patients; grade 3 anemia in 6 (16%) patients; and grade 3 or 4 thrombocytopenia in 4 (11%) patients. In addition, 4 patients experienced neutropenic fever. Non-hematologic side effects of note were grade 3 mucositis/stomatitis in 2 patients; grade 3(n=1) and grade 4 (n=1) cardiac dysfunction in 2 patients. IgG, IgA, IgM levels were all decreased after 2 cycles of chemotherapy. Further cycles did not affect immunoglobulin levels. Of the 34 patients evaluable for response, 24 (71%) achieved complete remission, 7 (21%) achieved partial remission, 1 (3%) had stable disease, and 2 (6%) had progression of disease. Conclusion: The mid study evaluation confirms that R-CHOP given every 15 days with GM-CSF (sargramostim) administered on days 3 through 13 of each cycle provides promising response rates with tolerable toxicity. Disclosures: Tulpule: Genzyme, I am the PI on this study funded by Genzyme.: Research Funding. </jats:sec