bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of of the Hsp-90 inhibitor, KOS-1022 (17-DMAG), in patients with refractory hematological malignancies
Authors: Lancet J. , Gojo I. , Baer M. , Burton M. , Klein M. , Nowadly C. , Gorre M. , Zhong Z. , Johnson R. G. , Hannah A. L.
Published: March 2020

2081

Background: Disruption of Hsp90-client protein heterocomplexes leads to degradation of a variety of oncoproteins. KOS-1022, an Hsp90 inhibitor and water-soluble geldanamycin derivative, is in trials in patients with solid tumors. Compared to a prior geldanamycin derivative (17-AAG), KOS-1022 is ∼3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies on the same schedule). Primary study objectives: establish safety and MTD of KOS-1022 in patients with advanced hematologic malignancies; characterize PK and PD. Methods: Escalating doses of KOS-1022 are given IV over 1 h twice weekly for 2 out of 3 weeks. Plasma KOS-1022 concentrations (1st and 4th infusion, Cycle 1) are quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts undergo flow cytometry to quantify Hsp70/90, pAKT/total AKT, markers of apoptosis and proliferation. Response in AML pts used IWG criteria. Results: 13 pts have been enrolled at doses of 8 (n=4), 16 (n=6), 24 (n=1) and 32 mg/m2 (n=2). All were AML (except 1 CML). Most (n=11) patients had 2–3 prior induction regimens. DLT was seen in 2 pts at 32 mg/m2 (acute myocardial infarction and elevation of troponin). Both patients had significant co-morbidity, including (1) prior myocardial infarction and (2) progressive AML with a similar troponin elevation during induction chemotherapy prior to study. Common drug-related toxicities (all Grade 1–2): fatigue, nausea, diarrhea and arthralgias. From 8 to 32 mg/m2, approximately linear PK was observed. Mean terminal half-lives varied from 13.0–31.2 hours. Day 1 clearance for 8, 16 and 32 mg/m2 was 5.6, 9.7 and 10.8 L/hr/m2; mean Vz (L/m2) for these groups were 238, 433 and 489. Although pre-infusion drug was quantifiable on Day 11 in most patients, Day 11/Day 1 AUC0–25h ratio was 0.96. Activity in AML: 2 CRi and 1 SD x 9 cycles were observed. Comparing BMAs taken at Day 8 and Day 15 to baseline: decreased Hsp90 (41% to 13%), increased Hsp70 (8% to 84%) with decreased pAKT (Ser), pAKT (Thr) and total AKT in CD34+ cells. Conclusions: KOS-1022 appears to be well tolerated, with preliminary signs of clinical and biologic activity in refractory leukemia. MTD has not been defined. Plasma PK is linear over this dose range.

[Table: see text]
A dose-escalation trial of GM-CSF-gene transduced allogeneic prostate cancer cellular immunotherapy in combination with a fully human anti-CTLA antibody (MDX-010, ipilimumab) in patients with metastatic hormone-refractory prostate cancer (mHRPC)
Authors: Gerritsen W. , Van Den Eertwegh A. J. , De Gruijl T. , Giaccone G. , Scheper R. J. , Lowy I. , Levy E. , Hege K. , Sacks N.
Published: March 2020

2500

Background: A Phase 1 trial is underway to study the combination of GM-CSF-gene-transduced allogeneic prostate cancer cellular immunotherapy (GVAX immunotherapy (IT) and ipilimumab in patients (pts) with mHRPC. Ipilimumab is a fully human IgG monoclonal antibody specific to the CTLA-4 receptor on T cells that augments immune responses by blocking the inhibitory CTLA-4/B7 interactions. Pre-clinical studies of antibodies to CTLA-4 in combination with GM-CSF secreting tumor cell vaccines demonstrate potent synergy. Methods: Eligible pts have documented mHRPC and are chemotherapy-naïve. All pts receive a 500 million cell priming dose of GVAX IT on day 1 followed by bi-weekly intradermal treatments (tx) of 300 million cells for a 24 week (wk) period. Ipilimumab is administered every 4 wks starting on day 1 for the same period. Pts are enrolled in cohorts of 3; each cohort is assigned an escalating dose of ipilimumab: 0.3, 1, 3 or 5 mg/kg. PSA is measured every 4 wks, and tumor assessments performed every 12 wks. 15 pts will be enrolled at the maximum tolerated dose. Pts are followed for disease progression and survival. Results: Ten pts have been enrolled. All 6 pts in Cohorts 1 and 2 have completed tx and are in follow-up; 5 of 6 completed all planned tx. Three pts in Cohort 3 have completed 75% of tx and are on-going. One pt in Cohort 4 has completed 25% of tx and is on-going. No dose-limiting or immune mediated toxicities have been observed. The most common adverse event is injection site reaction which occurs in 100% of pts. PSA responses by NCI working group criteria include 1 partial response (PR), 4 stable disease (SD), and 4 progressive disease (PD). Of note, 3 PD occurred in Cohort 1; 2 SD and 1 PD occurred in Cohort 2, and 1 PR and 2 SD occurred in Cohort 3. Any decline in PSA was evident within 2–4 wks of initiating tx. Conclusions: The combination of GVAX IT and ipilimumab appears well-tolerated in pts with mHPRC. These preliminary data suggest a relationship between PSA response and the dose level of ipilimumab in combination with GVAX IT.

[Table: see text]
A phase I study of ultra low dose interleukin-2 (IL-2) and stem cell factor (SCF) in patients with cancer and or HIV infection
Authors: Benson D. M. , Shah M. , Freud A. , Ferketich A. , Dezube B. J. , Bernstein Z. P. , Caligiuri M. A.
Published: March 2020

2503

Background: HIV infection depletes crucial lymphocyte subsets and often culminates in patients’ demise due to infectious or malignant complications. We have shown in previous work that ultra low dose interleukin-2 (IL-2) expands natural killer (NK) cells and other lymphocyte subsets in patients with AIDS-associated malignancies. Preclinical work by our group has demonstrated that CD56bright NK cells, an important source of interferon-γ, constitutively express the c-kit receptor and proliferate synergistically in vitro and in vivo in response to IL-2 and stem cell factor (SCF) presented together. To determine the safety, toxicity, and immune modulatation of IL-2 and SCF in patients, we report a first-in-man Phase I trial of this combination of cytokines in patients with HIV and HIV-associated malignancies. Methods: Eligible adults had a history of cancer and HIV or an AIDS defining illness, Karnofsky score > 70%, CD4 T-cell count > 20/mm3, and had to be on HAART therapy. Patients received IL-2 subcutaneously (SQ) daily at 900,000 IU/m2 (cohort 1) or 450,000 IU/m2 (cohorts 2 and 3) except Sunday and SCF (SQ) three times a week (at 5 mcg/kg/d or 10 mcg/kg/d) for 8 weeks. Toxicities and side effects of therapy were closely monitored. Changes in lymphocyte subsets were assessed by flow cytometry. Results: 13 patients (median age = 42, range 33–62) with cancer and HIV (5) or AIDS (8) were enrolled. 10 patients completed therapy, whereas three exhibited the grade 3 dose limiting toxicity (DLT) of fatigue and withdrew. Treatment led to statistically significant increases in NK cells (2.2-fold, p = 0.02) and regulatory T cells (Tregs) (6-fold, 0.005). These were similar to a previous study using a slightly higher dose of IL-2 alone (1 million IU/m2) in which NK were expanded 1.6 fold (p = 0.02) and Treg were expanded nearly 9-fold (p = 0.0003). Conclusions: Simultaneous administration of IL-2 and SCF is safe and well tolerated. The maximum tolerated doses of IL-2 and SCF were 450,000 IU/m2 and 5 mcg/kg/d respectively. Fatigue was the DLT. A trend towards preferential expansion of CD56bright NK cells as opposed to Tregs was seen; however, these changes were not significantly different from changes in response to a similar ultra low dose of IL-2 alone.

No significant financial relationships to disclose.
In vivo efficacy of the CD40 agonist antibody CP-870,893 against a broad range of tumor types: Impact of tumor CD40 expression, dendritic cells, and chemotherapy
Authors: Gladue R. P. , Cole S. H. , Donovan C. , Paradis T. , Alpert R. , Natoli E. , Bedian V.
Published: March 2020

2514

Background: CP-870,893 is a fully human IgG2 CD40 agonist antibody currently in early clinical trials. In vitro studies demonstrate its ability to bind human CD40 and enhance dendritic cell costimulatory molecule expression and cytokine production. Methods: In order to assess its potential for cancer therapy, we evaluated the anti-tumor efficacy of CP-870,893 against several CD40pos and CD40neg human tumors in SCIDbeige mice. We specifically addressed the role of tumor CD40 expression, the impact of re-population with human dendritic and T cells on efficacy, and it’s potential to act in synergy with chemotherapeutic agents. Results: We demonstrate that a single i.p. injection of CP-870,893 (T1/2 ∼ 7 days) prevented the growth of several subcutaneous CD40pos tumors including two B cell lymphomas, the breast carcinoma BT-474, and the prostate tumor PC-3 (ED50 = 0.02 mg/kg; Ceff ∼100 ng/mL). Efficacy was demonstrated when CP-870,893 was administered at the time of tumor challenge, but was also observed when treatment was delayed until tumors were well established. Although efficacious against CD40pos tumors, CP-870,893 had no effect on the growth of CD40neg/low tumors unless mice were repopulated at the tumor site with both naïve human dendritic cells and T cells. In these repopulated animals, i.p. administration of CP-870,893 inhibited the growth of a CD40low colon carcinoma and a CD40neg erythroleukemic tumor (ED50 = 0.005 mg/kg). The presence of human T cells and dendritic cells at the tumor site also improved the activity of CP-870,893 against CD40pos tumors, reducing the ED50 and Ceff >10-fold as compared to its effects in the absence of these cells, suggesting a synergy between direct CD40 mediated tumor killing and immune activation. Further, when administered as part of a combination treatment with a sub-optimal dose of cisplatin, improved activity was observed which resulted in tumor regression. Conclusions: These studies demonstrate the potent, broad-spectrum anti-tumor activity of CP-870,893 through both direct and immune mediated effects, its increased efficacy when co-administered with chemotherapeutic agents, and suggest its potential utility as a therapy for human cancer.

[Table: see text]
The in vivo targeting of tumor antigens to DCs by administration of transduced autologous lymphocytes results in robust and prolonged immunization: Pre-clinical validation and results of a pilot clinical studies of vaccination for metastatic melanoma
Authors: Russo V. , Cipponi A. , Fontana R. , Maggioni D. , Ciceri F. , Lunghi F. , Bregni M. , Bordignon C. , Traversari C.
Published: March 2020

2525

Background: Genetically-modified-lymphocytes (GML) can induce a specific immune response against the transgene product (HSV-TK), when injected into immunocompetent patients (Science 276:1719, 1997). In tumor-bearing mice the infusion of tumor-associated-antigen (TAA)-transduced lymphocytes induced protective immunity and long-term memory. In this experimental setting, the T-cell effectors were generated by a cross-presentation pathway, mediated by host dendritic cells (DCs). Indeed, DCs isolated from lymph nodes of treated mice contained fragments of labeled GML and were able to elicit antigen-specific responses ex vivo. Methods: To validate this novel vaccination strategy in humans, we treated 10 patients affected by stage IIIc/IV MAGE-A3+ melanomas with escalating doses of autologous GML expressing MAGE-A3 and the tracer antigen HSV-TK. HSV-TK allows to monitor the immune status of the patients. Immune responses were monitored by DTH and in vitro T cell assays (semi-quantitative recall assays and ELISPOT). Tumor status was monitored by conventional imaging analyses. Results: No toxicity was reported. From the 10 patients, 9 were clinically evaluable because responding to the tracer antigen HSV-TK. We observed one complete response with vitiligo surrounding the lesions and one long lasting stable disease (50 mo). Moreover, one patient with no evidence of disease remained free of disease at >48 mo. The 3 responding patients experienced both DTH reactivity to MAGE-A3 and sustained increase of circulating CD8+ and CD4+ MAGE-A3-specific effectors. The immune response was long lasting since MAGE-A3-specific effectors were still detectable both in vivo and in vitro 1 year after the last vaccination. Conclusions: We describe a new method for in vivo loading of TAA on DCs that may circumvent the limitations of ex vivo manipulation of DCs. Genetically modified lymphocytes, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice and in melanoma patients, resulting in the generation of TAA-specific effectors that correlate with clinical benefit.

[Table: see text]
A randomized pilot study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen independent prostate cancer
Authors: Arlen P. M. , Gulley J. L. , Parker C. , Skarupa L. , Pazdur M. , Tsang K. Y. , Schlom J. , Dahut W. L.
Published: March 2020

2531

Background: Docetaxel has activity against androgen insensitive prostate cancer (AIPC) and preclinical studies have demonstrated that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine: if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to a prostate cancer vaccine in patients with metastatic AIPC; secondary endpoints werewhether vaccine could be given safely with docetaxel, and the clinical outcome of the treatment regimen. Methods: The vaccination regimen was composed of (1) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (2) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (3) sequential booster vaccinations with recombinant fowlpox virus containing the PSA gene (rF-PSA). Patients received GM-CSF with each vaccination. Twenty-eight patients with metastatic AIPC were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. An ELISPOT assay for IFN-gamma production was used to monitor immune responses for PSA-specific T cells. Results: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer associated tumor antigens were also detected post-vaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median PFS on docetaxel was 6.1 months after receiving vaccine compared to 3.7 months with the same regimen in a historical control. Conclusions: This is the first clinical trial to demonstrate that docetaxel can be administered safely with immunotherapy, and without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.

No significant financial relationships to disclose.
Early results of a phase I clinical trial of an Ii-Key/Her2/neu MHC class II peptide-based vaccine in breast cancer patients
Authors: Mittendorf E. A. , Khoo S. , Storrer C. E. , Harris K. A. , Jama Y. H. , Dehqanzada Z. A. , Murray J. L. , Shriver C. D. , Von Hofe E. , Ponniah S. , Peoples G. E.
Published: March 2020

2532

Background: HER2/neu is over-expressed in breast cancer (BCa) and is the source of immunogenic peptides currently being evaluated in clinical trials as cancer vaccines. Ii-Key is a 4-amino-acid modification of peptides that has been reported to increase their occupancy of MHC class II molecules and enhance CD4 T cell responses. We are currently conducting a phase I clinical trial with an Ii-Key/HER2/neu MHC class II peptide (AE37) in BCa patients. Methods: The dose escalation safety trial design is for 3 groups of 3 patients to receive either 100, 500, or 1,000 μg of AE37 with 250 μg of GM-CSF in 6 monthly inoculations. Six additional patients will then be vaccinated at the optimal dose. Local and systemic toxicity is monitored and graded by the Common Toxicity Criteria. Immunologic response is monitored by peptide-stimulated proliferation (3H-thymidine incorporation) and ELISPOT (IFN-γ) assays for both AE37 and AE36 [the unmodified peptide HER2 776–790 (GVGSPYVSRLLGICL)]. Thus far 6 BCa patients have been vaccinated. Results: The 100μg dose group has completed all 6 vaccinations with maximum local and systemic toxicities of grade 2 and 1, respectively. All 3 patients developed increasing peptide-specific proliferation post-vaccination to both AE37 and AE36. ELISPOT responses were more variable with 1 minimal responder (30 IFN-γ spot-forming cells (SFC)/106 cells), 1 moderate responder (600 IFN-γ SFC/106 cells), and 1 good responder (1500 IFN-γ SFC/106 cells) post-vaccination. The 500μg dose group has thus far experienced earlier and larger local reactions but limited systemic toxicity. All 3 patients have demonstrated >1500 IFN-γ SFC /106 cells after just 2 inoculations. Peptide-specific proliferation after 2 inoculations has ranged between 3200–11500 cpm for the 500μg patients compared with 1200–2000 cpm after 6 inoculations for the 100μg dose group. Conclusions: AE37 appears to be safe and well-tolerated. A dose-dependent immunologic response has been demonstrated to the Ii-Key modified peptide as well as the naturally occurring sequence. These encouraging early results suggest that AE37 may prove to be useful as a CD4-specific vaccine either alone or in combination with CD8-specific HER2/neu peptides for improved cancer immunotherapy.

[Table: see text]
Systemic modulatory effects of the treatment with IL-2 of lung metastasis
Authors: Diaz D. , Chara L. , Chevarria J. , Navas V. , Esteban E. , Carballido J. , Muñoz A. , Torregrosa Z. , Arroyo M. , Alvarez-Mon M.
Published: March 2020

2560

Background: IL-2 is a drug that is employed in the treatment of several tumors due to its capacity of restore or increase the regulatory and effector function of the immune system. These effects have been demonstrated with the administration of the drug by intravenous and subcutaneous ways. Recently, it has been observed that the inhaled IL-2 administration is effective in the treatment of lung and renal cell carcinoma metastasis. However, it is unknown if this therapeutic effect is accompanied of systemic and local modulatory effects. Objectives: To compare spontaneous and mitogen-induced apoptosis in lymphocytes of renal carcinoma patients before and after treatment with inhaled IL-2. Methods: Peripheral blood mononuclear cells were purified from 7 patients with renal carcinoma before and after treatment with inhaled IL-2. The cells were characterized in a FACScalibur analyzer using fluorocrome-labeled monoclonal antibodies. The AI (or percentage of apoptotic cells, AI x 100) was calculated for T-cells expressing CD3, CD4, CD8, CD56, HLA-DR, CD25 and CD45RO/CD45RA antigens and NK-cells (CD3-CD56+ or CD3-CD16+). These AI were determined after 24 hours of culture under two conditions: without exogenous apoptosis inducers and in the presence of phytohemagglutinin. Comparisons between patients were carried out using the Wilcoxon test and were considered significant when p < 0.05. Results: A significant decrease in spontaneous ex vivo apoptosis was found in peripheral blood lymphocytes from renal carcinoma patients after treatment with inhaled IL-2 with respect to pretreatment values. This decrease occurred in T-cells and also in CD45RO expressing cells from both CD4+ and CD8+ subsets. A decrease of apoptosis was also observed in CD25+ expressing cells from CD3+, CD4+ and CD8+ subsets. A decrease in AI was found in mitogen induced apoptosis of CD25+ cells from CD3+, CD4+ and CD8+ subsets. Conclusions: The treatment with inhaled IL-2 has immunomodulatory effects that are observed at systemic level reducing the apoptosis of cells from several memory and activated T-cell subsets.

No significant financial relationships to disclose.
Blocking the regulatory T cell molecule LAG-3 augments in vivo anti-tumor immunity in an autochthonous model of prostate cancer
Authors: Drake C. G. , Kelleher C. , Bruno T. , Harris T. , Flies D. , Getnet D. , Hipkiss E. , Maris C. , Grosso J.
Published: March 2020

2573

Background: LAG-3 is a CD4 homolog expressed on activated T cells, NK cells, tumor infiltrating lymphocytes (TIL), and plasmacytoid dendritic cells. Recently, we showed that LAG-3 was relatively overexpressed in specific T cells rendered unresponsive in vivo by the presence of cognate self-antigen. These anergic T cells display regulatory function both in vitro and in vivo, and blockade of LAG-3 with a non-depleting monoclonal antibody significantly mitigates their regulatory T cell activity. Methods: Using a novel model of prostate cancer in which a tumor-specific antigen is expressed in autochthonous tumors, we tested whether treatment with a non-depleting anti-LAG-3 antibody affected trafficking and function of tumor-specific T cells. Results: LAG-3 blockade significantly augments specific CD8 T cell trafficking to antigen-expressing tumors, but not to normal tissue. Most significantly, LAG-3 blockade functionally reversed CD8 T cell tolerance as assayed by an in vivo cytotoxic T lymphocyte (CTL) assay. Combining LAG-3 blockade with specific anti-tumor vaccination results in a dramatic increase in activated CD8 T cells in the tumor parenchyma. Conclusions: Taken together, these data support the concept that treatment with a LAG-3 blocking antibody may significantly delay disease progression in patients with cancer. We have recently generated a panel of monoclonal antibodies directed against human LAG-3; several of these antibodies significantly augment human T cell responses in vitro.

No significant financial relationships to disclose.
Vaccine for prevention of breast cancer
Authors: Deisseroth A. , Tang Y. , Maynard J. , Akbulut H.
Published: March 2020

2580

Background: Women with high risk breast cancer still succumb to their disease despite existing programs of adjuvant therapy. Thus, new approaches for adjuvant therapy are needed. Her-2-Neu overexpression on a breast cancer cells correlates with recurrence, metastasis and resistance to chemotherapy and radiation therapy. The immune response is tolerant of tumor associated antigens (TAA) like Her-2-Neu since they have been present on epithelial cells since birth. The immune response to vaccines in women with breast cancer is limited by the diminished number of CD4 and CD8 T cells and qualitative defects of CD4 cells in individuals above the age of 50. Methods: The following strains of mice were vaccinated: 6–8 week old hMUC-1.Tg mice, and rH2N.Tg mice, as well as 18 month and 2 month old C57BL/6J mice, by injecting subcutaneously the Ad-sig-TAA/ecdCD40L vector prime followed by sc injections of the TAA/ecdCD40L protein boost. Results: Vaccination of 18 month old mice with the Ad-sig-TAA/ecdCD40L vector prime protein boost produce regressions of TAA positive sc tumor and a 5 fold increase in antigen specific spleen cells, a 10X increase in subcutaneous tumor nodules of antigen specific effector CD8 T cells by tetramers, and a 2X decrease of CD4+CD25+FOXP3+ cells. Vaccination of rH2N.Tg mice starting at 6 weeks with the Ad-sig-rH2N/ecdCD40L vector prime/protein boost prevented the development of breast cancer in 50% of the mice. The Ad-sig-hMUC-1/ecdCD40L vector prime/ hMUC-1/ecdCD40L protein boost induced hMUC-1 specific antibodies in hMUC-1.Tg mice which bound to human breast cancer specimens. The rH2N/ecdCD40L vector prime/protein boost vaccine suppressed growth of rH2N positive tumor cells and this effect was potentiated by concomitant administration of chemotherapy. Conclusions: These results suggest that the Ad-sig-TAA/ecdCD40L platform can be used to suppress the growth of existing breast cancer even in old mice and prevent the development of breast cancer. We are preparing a phase I clinical trial of this approach in the setting of breast cancer patients who have failed first line adjuvant therapy. In this trial, the vaccine will be added to established salvage therapy and both in vivo evaluations of tumor response, in vitro assays of immune response and toxicity will be measured.

No significant financial relationships to disclose.
Effect of dasatinib, a SRC kinase inhibitor, on lung cancer cells with defined epidermal growth factor receptor status
Authors: Haura E. B. , Song L. , Lee F. , Jove R.
Published: March 2020

3019

Background: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict sensitivity to small molecule inhibitors of EGFR such as gefitinib and erlotinib. Importantly, mutant EGFR selectively activates Akt and STAT pathways that are important in NSCLC cell survival. SRC-family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules such as PI3K/PTEN/Akt and STATs. Despite the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and SRC proteins, and evidence of elevated SRC activity in human lung cancers, the effect of SRC inhibition on cell fate is unknown. Methods: We evaluated the anti-tumor efficacy of a novel orally bioavailable SRC-ABL inhibitor dasatinib (BMS-354825) in non-small cell lung cancer cell lines with defined EGFR status including wildtype EGFR and mutant EGFR sensitive to gefitinib. Western blotting was used to evaluate the effect of dasatinib on downstream signaling pathways and in vitro assays were used to evaluate the effect cell cycle, apoptosis, and cell invasion. Results: Our results show that cell fate (death versus growth arrest) in lung cancer cells exposed to a SRC inhibitor is dependent on EGFR status. Dasatinib reduces mutant EGFR lung cancer cell viability through the induction of apoptosis and G1 cell cycle arrest while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of phosphorylated Akt and Stat3 survival proteins. In cell lines without EGFR mutation, dasatinib induces a G1 cell cycle arrest with associated changes in cyclin D and p27 proteins as well as inhibits activated FAK and prevents tumor cell invasion. Conclusions: Our results demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers through disruption of cell growth, survival and tumor invasion. Our results suggest EGFR status is critical in deciding cell fate in response to SRC inhibition.

[Table: see text]
Bevacizumab plus erlotinib in patients (pts) with carcinoma of unknown primary site: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Hainsworth J. D. , Spigel D. R. , Thompson D. S. , Shipley D. L. , Zubkus J. D. , Toomey M. A. , Burkett E. , Greco F. A.
Published: March 2020

3033

Background: Targeted therapies inhibiting tumor angiogenesis or the epidermal growth factor pathway have demonstrated efficacy in a variety of solid tumors. In this multicenter phase II trial, we evaluated the efficacy of combined targeted therapy with bevacizumab plus erlotinib in pts with carcinoma of unknown primary site. Methods: Eligibility criteria included: metastatic adenocarcinoma or poorly differentiated carcinoma of unknown primary site; 1 or 2 previous chemotherapy regimens (previously untreated pts were eligible only if considered poor candidates for chemotherapy due to advanced liver or bone metastases); measurable disease; ECOG PS 0–2; no previous anti-angiogenic or EGFR inhibitor therapy; no active brain metastases; no active thromboembolic disease or bleeding abnormalities; adequate organ function; informed consent. All pts received bevacizumab 10mg/kg IV q 2 weeks and erlotinib 150mg PO daily. Pts were evaluated for response after 8 weeks; treatment was continued until tumor progression. Results: 51 pts entered this clinical trial between 4/04 and 7/05. Pt characteristics: median age 57; male/female, 22/29; ECOG 0/1/2, 5/43/3; previous chemotherapy, 75%. 49 pts (96%) received at least 2 months therapy and were evaluable for response. Objective responses occurred in 4 pts (8%) (all ongoing at 5+ - 19+ months); 30 pts (59%) had stable disease/minor response. After median follow-up of 13 months, median progression-free survival for the entire group is 6.2 months. Median overall survival is 8.9 months, with 42% of pts alive at 1 year. 1-year survival for previously treated vs. untreated pts: 41% vs. 46%. Toxicity with this regimen was consistent with previous reports; other than fatigue (12%), no grade 3/4 toxicity was observed in > 10% of pts. Conclusions: The combination of bevacizumab and erlotinib has activity in pts with carcinoma of unknown primary site. Progression-free and overall survival results appear superior to our previous second-line results using a variety of chemotherapy regimens, and are similar to results with first-line chemotherapy. Future trials will evaluate bevacizumab/erlotinib as part of first-line therapy.

[Table: see text]
Letrozole (L) with bevacizumab (B) is feasible in patients (pts) with hormone receptor-positive metastatic breast cancer (MBC)
Authors: Traina T. A. , Rugo H. , Caravelli J. , Yeh B. , Panageas K. , Bruckner J. , Norton L. , Park J. , Hudis C. , Dickler M.
Published: March 2020

3050

Background: Bevacizumab added to chemotherapy (CRx) prolongs PFS in pts with MBC. Data suggest that estrogen (E2) modulates VEGF-induced angiogenesis in physiologic and pathologic conditions. E2-induced VEGF expression may promote breast cancer growth therefore combination therapy with an aromatase inhibitor (AI) and an antibody to VEGF may be more effective than either agent alone. We performed a feasibility study testing B with L for the treatment (tx) of hormone receptor-positive MBC. Methods: Eligible pts have MBC and are candidates for AI therapy. Prior non-steroidal AI (NSAI) use without progression is permitted. Premenopausal pts undergo ovarian suppression/oophorectomy prior to tx. Therapy consists of L (2.5 mg daily) and B (15 mg/kg IV q3 weeks). The primary endpoint is frequency of Grade (Gr) 4 toxicity. Secondary endpoints include response rate, stable disease (SD) ≥ 6 mo and time to tumor progression. Using a two-stage design, 19 pts were accrued. Because <3 pts had Gr 4 toxicity, the 2nd stage is now enrolling an additional 23 pts. If <5 of the 42 pts have Gr 4 toxicity, the regimen will be considered feasible. Results: Thirty two pts are currently accrued and 28 are now evaluable. Medians: Age 49.5 yrs (32–77) and ECOG PS 0 (0–1). Sites of MBC: bone only 11/28, visceral 16/28, chest wall/soft tissue/lymph nodes 11/28. All are ER and/or PR (+); none are HER2 (+). Prior therapy: adjuvant CRx 20; adjuvant tamoxifen 14. Twenty five pts received an NSAI as first-line tx of MBC, starting a median of 23 wks (1–213) before B. Three pts received first-line tamoxifen; one pt had prior CRx for MBC. After a median of 8 cycles (1–20), tx-related toxicities: Gr 2: hypertension (HTN) 4, headache (HA) 4, proteinuria 3, fatigue 6, joint pain 5, hot flashes 1, epistaxis 1; Gr 3: HTN 5, HA 1, proteinuria 1. There has been no tx-related Gr 4/5 toxicity. Tx-related withdrawals: HTN 1 and headache 1. Twenty five pts are evaluable for response: PR 2, SD ≥ 6 mo 13, SD 4, progression 6. Conclusions: Combination L and B is well tolerated and will be studied in a randomized CALGB trial. Circulating endothelial and tumor cell data is reported separately. Supported in part by Genentech and Novartis.

[Table: see text]
Preliminary pharmacogenetic evaluation of toxicity data in the prospective multicentre EORTC trial 40015 in metastatic colorectal cancer (CRC)
Authors: Aust D. , Kohne C. , Goekkurt E. , De Greve J. , Hartmann J. , Van Cutsem E. , Debois M. , Bethe U. , Lutz M. P. , Stoehlmacher J.
Published: March 2020

3072

Background: EORTC phase III study 40015 was initiated in 2003 to compare capecitabine (C) + irinotecan (CPT-11) vs 5FU/LV/irinotecan ± celecoxib in 1st line treatment of mCRC. The study was suspended after enrollment of 85 pts due to 8 fatal events not related to disease progression, 4 of which included thrombo-embolic events. Purpose: To test whether genetic polymorphisms involved in metabolism of the drugs are related to the increased toxicity observed in the study. Methods: 71 pts signed informed consent for genetic analyses and material was available for 58 pts. DNA was extracted from normal colonic mucosa or peripheral leukocytes. Polymorphisms were determined using PCR-based RFLP and direct sequencing. Genotypes known to be associated with increased toxicity (diarrhea, mucositis, leucopenia) were classified as unfavorable. Results: Unfavorable genotypes were distributed equally between C+CPT-11 and LV/5FU+CPT-11 arms. Baseline characteristics and treatment duration were similar in the pts with or without unfavorable genotypes. Unfavorable genotypes of thymidylate synthase (TS-5; TS-3) and UDP-glucuronosyltransferase 1A1 (UGT1A1) were associated with increased grade 3/4 toxicity. 18/35 (51%) pts with unfavorable UGT1A1 genotype experienced toxicity grade 3/4 compared to 3/23 (13%) pts with favorable genotype. 16/36 pts (44%) with unfavorable TS-5 genotype showed toxicity grade 3/4 compared to 5/22 (23%) pts with favorable genotype. Toxicity grade 3/4 was observed in 18/41 (44%) pts with unfavorable TS-3 genotype and 3/17 (18%) pts with favorable genotype. Increasing grade 3/4 toxicity rates were observed in the pts expressing 0/1 (2/16 [13%]), 2 (7/24 [29%]) or 3 (12/16 [75%]) unfavorable genotype(s) (p=0.0001). Among the 4 pts who died of a thrombo-embolic event, only one has been analysed at this stage and showed a Factor (V) Leiden mutation linked to 10-fold increased risk for thrombo-embolic events. Analyses are ongoing and complete data will be available for presentation. Conclusion: Our data suggest an association between polymorphisms of TS and UGT1A1 and toxicity. No differences of pharmacogenetic patterns were observed that could explain the increased rate of fatal events in the C/CPT-11 arm.

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Final results of a prospective multicenter study on the prevalence and genotype/phenotype correlation of the dihydropyrimidine dehydrogenase (DPD) gene exon-14 skipping mutation in patients treated with 5-fluorouracil (5-FU) chemotherapy
Authors: Raida M. , Friedrich A. , Borris H. , Niederwieser D. , Behnke D. , Kliche K. O. , Ruffert K. , Schalhorn A. , Schwabe W. , Hausler P.
Published: March 2020

3076

Background: DPD represents the initial and rate-limiting enzyme in the catabolism of 5-FU. Deficiency of DPD has been linked to toxic side effects of 5-FU. The most common mutation of the DPD gene resulting in severe DPD deficiency is a G to A mutation in the GT 5’-splice recognition site of intron 14 (exon 14 skipping mutation). The corresponding mRNA lacks exon 14 and the enzymatic activity of the translated DPD protein is virtually absent. In a clinical setting heterozygous and homozygous carriers are being observed. Methods: We developed an RT-PCR based assay suitable for routine identification of the exon 14 skipping mutation. From February 2001 to October 2004 we performed an open, uncontrolled, prospective multicenter study to evaluate the prevalence and genotype/phenotype correlation of the exon 14 skipping mutation in patients treated with 5-FU chemotherapy. 1455 patients from 70 clinical centers in Germany were included in the study. Results: We identified 15 heterozygous carriers confirming a prevalence of 1% in the Caucasian population. For the analysis of 5-FU related toxicity WHO grades were ranked with a toxicity index revealing a significant higher toxicity in heterozygous compared to wildtype patients (p<0.0001). 50% of the heterozygote patients subsequently were treated with reduced doses of 5-FU. Nonetheless the positive predictive value of the screening test was still 50% indicating a strong correlation between genotype and phenotype. To identify patients in risk of severe 5-FU related toxicity we performed 5-FU pharmacokinetics in 12 heterozygous patients and 8 wildtype patients. All heterozygous patients showed a pathological 5-FU half-life with broad variations after intravenous bolus application of 450 mg/m2 5-FU while 75% of the wildtype controls had physiological results. Conclusions: We conclude that routine testing for the exon 14 skipping mutation and additional 5-FU pharmacokinetics for heterozygous patients prior to 5-FU treatment is an important step towards individually tailored therapy in cancer patients.

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Phase I dose escalation, pharmacokinetic, and biomarker study of imatinib mesylate plus capecitabine in advanced solid tumor malignancies
Authors: Favaro J. P. , Petros W. , Hong T. , Fernando N. , Bendell J. C. , Gockerman J. P. , George D. J. , Williams-Truax R. , Nixon A. , Yu D. , Hurwitz H.
Published: March 2020

3093

Background: Preclinical data have suggested at least additive antitumor effects when imatinib (I) and 5-FU are combined. The goals of this study were to determine the maximal tolerated dose for the combination of I and capecitabine (C) in solid tumor patients (pts), as well as to describe non-dose limiting toxicities (non-DLT), pharmacokinetics (PK), and pharmacodynamics (PDGFR inhibition in granulation tissue). Methods: 24 pts (12 M, 12 F) with solid tumor malignancies received C plus I using a 21 day (d) cycle. C was dosed BID for 14/21 d. I was dosed QD x 21d. Results: 24 of 24 pts were fully evaluable for toxicity and efficacy. 6 pts were treated at dose level 1 (C 1000 mg/m2 BID, I 300 mg QD). The only dose limiting toxicity (DLT) at dose level 1 was grade (gr) 3 diarrhea in 1 patient; however 5 of 6 pts required dose reductions in a subsequent cycle. Therefore, the next 18 pts were treated at dose level -1 (C 750 mg/m2 BID and I 300 mg QD). One DLT (gr 3 fatigue) was seen at dose level -1. Non-DLT gr ¾ toxicities at any point at dose level -1 were gr 4 anemia (n=1) and gr 3 lymphopenia (n=6). Toxicities requiring dose reductions at any point on dose level -1 occurred in 7/18 patients. Gr ½ toxicities found in > 10% of all patients at any point in the trial were anemia (46%), leukopenia (17%), neutropenia (21%), lymphopenia (29%), thrombocytopenia (29%), nausea (71%), anorexia (41%), edema (42%), diarrhea (38%), hand foot syndrome (33%), vomiting (33%), headache (25%), insomnia (25%), skin rash (25%), constipation (21%), stomatitis (17%), lightheadedness (13%), fatigue (13%), numbness/tingling (13%), taste change (13%), and elevated transaminases (13%). 1 pt with carcinoid tumor had a partial response. 1 pt with non-small cell lung cancer had a minor response, and 5/21 pts had stable disease as their best response. 1 pt had stable disease for 8 months and another pt was stable for 6 months. Conculsions: On a 21 d cycle, the recommended phase 2 dose of C plus I is C 750 mg/m2 BID for 14 d, and I 300 mg QD.

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Complete radiological response of colorectal liver metastases (LM) after chemotherapy: Does it mean cure?
Authors: Nordlinger B. , Brouquet A. , Penna C. , Julié C. , El Hajjam M. , Chagnon S. , Mitry E. , Rougier P. , Benoist S.
Published: March 2020

3501

Background: Most of patients with colorectal LM receive systemic chemotherapy. Complete response on imaging is considered a good indicator of the efficacy of chemotherapy. Whether complete radiological response is correlated to complete pathological response is not well known. The objective of this study was to determine the significance of complete radiological response of LM after chemotherapy. Methods: Between 1998 and 2004, 586 patients were treated in one institution for colorectal LM. 38 with the following criteria were included in the study: less than 10 LM before chemotherapy, disappearance of one or several LM on helical CT scan and ultrasound after chemotherapy, surgery with liver examination and intraoperative ultrasound within 4 weeks after imaging, no extra-hepatic disease, follow-up at least one year after surgery. Results: Overall, 66 LM disappeared on imaging after chemotherapy (38 patients). In 9 patients, persistent macroscopic disease was observed at surgery at the site of 20/66 (30%) LM although there were considered in complete response on imaging. In 15 patients, with no remnant disease at surgery, the sites of 15 initial LM were resected. Pathological examination of theses sites of LM considered in complete response showed the presence of viable tumor cells in 12/15 cases (80%). In 14 other patients, the sites of 31 initial LM, which were not visible at surgical exploration were left in place during surgery. After one year of follow-up, 23/31 (74%) LM considered in complete response had recurred in situ (11/14 patients). Overall, persistent macroscopic or microscopic residual disease or early recurrence in situ were observed in 55/66 LM (83%) with complete radiological response (32/38 patients). Conclusions: Complete radiological response in patients who have received chemotherapy is a useful tool to evaluate the effect of chemotherapy but it does not mean cure in most patients. This should be taken into account when considering multimodality treatment including chemotherapy and surgery.

No significant financial relationships to disclose.
Genetic polymorphisms, toxicity, and response rate in African Americans (AA) with metastatic colorectal cancer (MCRC) compared to Caucasians (C) when treated with IFL, FOLFOX or IROX in Intergroup N9741
Authors: Goldberg R. M. , McLeod H. L. , Sargent D. J. , Morton R. F. , Green E. M. , Fuchs C. , Ramanathan R. K. , Williamson S. K. , Findlay B. P. , Pitot H. C. , Alberts S. R.
Published: March 2020

3503

Background: The association between race & toxicity or response to systemic chemotherapy is poorly understood. We correlated relevent polymorphisms with toxicity & outcome data in AA & C patients (Pts) enrolled in N9741, a large randomized MCRC trial. Methods: Toxicity, response rate (RR), time to progression (TTP), overall survival (OS), & dose intensity (DI) were examined as a function of race in 1412 Pts enrolled on IFL, both full and reduced dose, FOLFOX, or IROX including 486 Pts with pharmacogenomic data. Accrual by race permitted comparison of C (n=1297) to AA (n=112). Results: C & AA were similar in disease extent, PS, gender, prior adjuvant treatment, and DI at cycles 1, 3, 6, or 12. The impact of race on RR, toxicity & the distribution of four relevent drug metabolism genotypes are in the table . AA had lower RR overall & in each treatment arm. Lower toxicity rates were seen in AA Pts, mainly due to less diarrhea, as measured by both CTC V2 & patient reported outcome data. These relationships were maintained in multivariate models adjusting for arm, age, gender, & PS. In these multivariate models, the odds ratio between RR and race was 1.72 (p=0.012) (29% AA vs 41% C) & for severe toxicity the odds ratio was 1.76 (p=0.006) (34% AA vs 48% C). Overall, race was not a significant predictor of TTP or OS (p > 0.50 for each). The hazard ratio comparing FOLFOX to IFL for C was 0.67 and for AA was 0.55. TTP for FOLFOX was superior to both IFL and IROX for both C & AA. Significant differences in pharmacogenetic variants were observed between C & AA, although the sample size for investigating the three-way combination of Rx, race, & pharmacogenomics is too small (36 AA) to draw definitive conclusions. Conclusions: It appears that AA have less toxicity & a lower RR than C when treated with standard MCRC regimens. Different frequencies of polymorphisms in genes relevent to drug metabolism may help explain these clinical differences.

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A randomized trial of first-line irinotecan/fluoropymidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C)
Authors: Fuchs C. , Marshall J. , Mitchell E. , Wierzbicki R. , Ganju V. , Jeffery M. , Schultz J. , Richards D. , Wang B. , Morrison M.
Published: March 2020

3506

Background: This multicenter, randomized study assessed efficacy & safety for 3 irinotecan/fluoropyrimidines combinations in previously untreated mCRC. In a 3 × 2 factorial design, we also assessed whether celecoxib added to chemotherapy (CT) improved CT efficacy and/or reduced toxicity. Methods: Pts were randomized to: FOLFIRI - irinotecan (I) 180 mg/m2, leucovorin (LV) 400 mg/m2, 5-FU bolus 400 mg/m2, & infusional 5-FU 2400 mg/m2 over 46 hours q 2 wks; modified IFL (m-IFL) - I 125 mg/m2, LV 20 mg/m2, & bolus 5-FU 500 mg/m2 wkly × 2, q 3 wks; or CapeIri - I 250 mg/m2 day 1 & capecitabine 1000 mg/m2 po BID × 14 days, q 3 wks. Pts were also randomized to concurrent celecoxib (400 mg po BID) or placebo in a double-blind fashion. Time to progression (TTP) was the primary endpoint. Results: 430 pts were enrolled from 2/03 to 4/04, prior to an amendment that added bevacizumab to CT arms. Baseline characteristics were balanced. TTP for FOLFIRI (median = 8.2 mos) was significantly better than for either m-IFL (6.0 mos; p = 0.01) or CapeIri (5.7 mos; p = 0.01). Overall survival (OS) also favored FOLFIRI (median = 23.1 mos) compared to either m-IFL (17.6 mos; p=0.10) or CapeIri (18.8 mos; p = 0.19). Common grade ≥ 3 toxicities are listed below. CapeIri had the highest rates of nausea, vomiting, diarrhea, dehydration & hand-foot syndrome, whereas FOLFIRI had lower rates. Among all 430 pts, median TTP did not differ for pts randomized to celecoxib compared to placebo (6.9 vs 6.9 mos; p=0.71). Median OS was also similar for celecoxib vs placebo (19.5 vs 18.8 mos; p=0.63). CT toxicities did not differ for celecoxib vs placebo. Rates for MI/stroke were 1.5% for celecoxib and 1.9% for placebo. Conclusions: First-line FOLFIRI offers a superior TTP when compared to m-IFL or CapeIri; OS & toxicity analyses also favored FOLFIRI. Celecoxib neither improved CT efficacy nor reduced CT toxicity. Updated survival data & data on pts enrolled after the addition of bevacuzimab will be presented.

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