julilili42/papers huggingface dataset:
Final results of a phase I/II study in patients with pancreatic cancer, malignant melanoma, and colorectal carcinoma with trabedersen.
2012-05-20

4034 Background: TGF-β2 overexpression in solid tumors triggers key cancer pathomechanisms, i.e. suppression of antitumor immune responses system and metastasis. Trabedersen specifically inhibits TGF-β2 expression. In the clinical Phase I/II study we evaluate MTD, safety, pharmakokinetics (PK), and efficacy of i.v. trabedersen in patients with advanced tumors. Methods: A total of 61 patients with pancreatic cancer (PancCa, n=37), malignant melanoma (MM, n=19), or colorectal carcinoma (n=5) were treated with i.v. trabedersen as 2 nd to 4 th -line therapy with escalating doses in 2 treatment schedules. (1 st schedule: 7d on, 7d off; 2 nd schedule: 4d on, 10d off; up to 10 cycles). Within the 1 st schedule, the MTD was established at 160 mg/m 2 /d. In the 2 nd schedule dose-escalation was stopped before reaching MTD. In the Phase II-part of the study further PancCa and MM patients were treated with 140 mg/m 2 /d. For assessment of PK parameters, plasma time profiles were analyzed for trabedersen and its n-1 to n-5 metabolites by non-compartimental analysis. Results: Trabedersen was safe and well-tolerated. The only expected adverse reaction identified is non-serious and transient thrombocytopenia. Only 2 SAEs (gastrointestinal hemorrhage und pyrexia) were considered as possibly related to study medication. Further clinical development will focus on PancCa patients receiving 140 mg/m 2 /d trabedersen as 2 nd -line treatment. Survival analysis of these patients revealed a mOS of 13.4 months (n=9; 95% CI: 2.2, 39.7). One PanCa patient had a complete response of liver metastases and is still alive after 75 months. Promising efficacy data were also seen in MM patients enrolled into the last cohort (140 mg/m 2 /day) with a current mOS of 9.3 months (n=14; 95% CI: 6.5, 12.2). PK analyses showed for both treatment schedules that exposure to trabedersen was in the expected range for all doses and half-life of trabedersen (1.12 to 2.08 hrs) as well as clearance (2.22-4.37 L/h*m 2 ) were independent of dose. Conclusions: Trabedersen showed excellent safety and encouraging survival results in the Phase I/II clinical study. A randomized, active-controlled study in 2 nd line stage IV PanCa patients is in preparation.
An open-label, multicenter safety study of vemurafenib (PLX4032, RO5185426) in patients with metastatic melanoma.
2012-05-20

8517 Background: Vemurafenib, a BRAF inhibitor, is associated with improved PFS and OS in patients (pts) with BRAF V600 -mutant metastatic melanoma (mM). We present preliminary safety and efficacy findings from a safety study of vemurafenib in pts with unresectable stage IIIC/IV mM with BRAF V600 mutations. Methods: Pts with untreated or previously treated stage IIIC/IV BRAF V600 mutation-positive (cobas 4800 BRAF V600 Mutation Test) melanoma were enrolled. Pts received continuous oral vemurafenib 960 mg bid. Primary study endpoint was safety; efficacy (RECIST V 1.1) was a secondary endpoint. Results: Of 1,964 screened pts between Mar and Sep 2011, 914 (47%) were enrolled and 834 were evaluable for safety. Median age was 53 (21–88 years), 55% males. Median time since first mM diagnosis was 7.6 months (0–18 years). At baseline, 80% of pts had ECOG PS 0–1, 11% ECOG PS 2 (missing 9%); 27% of pts had brain metastases, and 31% had elevated LDH. Most pts had received prior systemic therapy (70%) including ipilimumab (14%), MEK and BRAF inhibitors (2%). At data cut-off (Sep 30, 2011), median treatment duration was 68 days (1–223 days) with 87% of pts still on treatment. Of 834 pts, 553 (66%) to date have reported AEs. Of 553 pts reporting AEs, 88% were related to vemurafenib, 33% Grade 3, and 1.9% Grade 4. The most common (&gt;1%) Grade 3/4 AEs were rash (3.6%), arthralgia (3.1%), and cutaneous squamous cell carcinoma/keratoacanthoma (4.3%). Most common AEs (&gt;10%) of any grade were arthralgia (31%), rash (29%), fatigue (22%), photosensitivity (21%), nausea (15%), and were similar irrespective of brain metastases and ECOG PS. AEs caused treatment interruption in 141 (17%) pts. Of 109 pts who discontinued treatment (13%), main reasons for withdrawal were progressive disease (60%), death (20%), AEs (6%; most commonly arthritis and abdominal pain). Tumor assessments at Week 8 of treatment were available for 302/834 (36%) pts, 61% pts achieved CR or PR, and 29% had SD. Conclusions: In a setting representative of routine clinical practice, vemurafenib is seen to be well tolerated and both safety profile and activity resemble the phase I–III data although this analysis is limited by the study duration.
DETECT III: A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC).
2012-05-20

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.
Messenger RNA vaccination and B-cell responses in NSCLC patients.
2012-05-20

2573^ Background: Vaccination with mRNA is a novel technology in cancer immunotherapy. CV9201 consists of self-adjuvanted mRNA molecules (RNActive ) coding for five non small cell lung cancer (NSCLC)-associated tumor antigens (MAGE-C1, MAGE-C2, NY-ESO-1, BIRC5, 5T4). We report final results of a phase I/IIa trial of CV9201 in patients (pts.) with NSCLC. Methods: Pts. with stage IIIB/IV NSCLC with a response or stable disease after first-line chemotherapy or chemoradiation were eligible. Cohorts of 3 pts. were treated at three dose levels (400μg, 800μg and 1600μg CV9201) and observed for DLTs to select the highest tolerated dose for phase IIa. Primary endpoint was safety and tolerability; secondary endpoints were immune response, clinical efficacy and survival. Pts. received up to five vaccinations of CV9201 within 15 weeks. Antigen-specific immune responses against each of the 5 antigens were measured at baseline, and two weeks after the 3 rd and 5 th vaccination. Frequency of lymphocyte subsets and expression of activation and maturation markers were measured and retrospectively correlated with immunological and clinical parameters. Results: 46 pts. were included (9 phase I; 37 phase IIa); No DLTs occurred, and the 1600 μg dose was investigated in phase IIa. The most frequent related adverse events were mild to moderate injection site reactions and flu-like symptoms. 3 patients (7%) had potentially related grade 3 AEs (fatigue, injection site granuloma, asthma attack) and no related SAEs were reported. There were no objective responses. Data on PFS and survival will be presented. Antigen specific immune responses against at least one antigen were induced in 65% of pts. (39% cellular and 49% humoral). Consistently, a significant ≥2 fold increase of pre germinal center B cells (pGCB) was observed in 61% of pts. This increase of pGCB correlated significantly (p=0.0028) with increase of total CD4 effector T cells. Frequency of CD 4 T Reg cells did not increase during treatment. Conclusions: Vaccination with CV9201 has a favorable safety profile and induces T and B cell responses against all included antigens. Vaccine-induced increase of pGCB is a new finding and might be used as a biomarker in cancer immunotherapy.
Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on PCR and survival: Results of the GeparTrio trial.
2012-05-20

1023 Background: We previously reported as a result of the GeparTrio phase III trial that response-guided neoadjuvant chemotherapy (CT) with TACx8 or TAC/NX, compared to TACx6, can improve survival especially in hormone-receptor (HR)-positive tumors. As this benefit could not be predicted by pathological complete response (pCR), better surrogate response markers are warranted. Methods: 2072 patients with operable or locally advanced breast cancer were treated with 2 cycles TAC before interim response assessment. Responders were randomized to additional TACx4 or TACx6 and non-responders to TACx4 or NXx4. We centrally measured Ki-67 in1165 pre-CT core biopsies and in 676 post-CT surgical samples. Counting patients with a pCR as having 0% Ki-67, 757 pre-/ post-CT pairs were available. Ki-67 percentage levels were grouped to low (0-15%), moderate (15.01-35%), and high (35.01-100%) according to cut-point finding analysis in a training and validation cohort. Results: pCR rates were 4.2%, 12.9%, and 29.0% in tumors with low, moderate, and high pre-CT Ki-67 levels (p&lt;0.0001). Pre-CT Ki-67 levels significantly predicted disease-free survival (DFS) (log rank p&lt;0.0001) overall, in the HR+ (p&lt;0.0001), but not in the HR- (p=0.5) subgroup. Post-CT Ki-67 levels correlated with DFS (p&lt;0.0001). Patients with low post-CT Ki-67 levels showed comparable outcome to patients with pCR. Patients with increased Ki-67 levels from before to after CT showed an impaired outcome compared to patients with stable or decreased Ki-67 levels (p&lt;0.0001). However, post-CT Ki-67 levels appeared to have more prognostic relevance than Ki-67 changes. Low post-CT Ki-67 levels were not more frequent after response-guided treatments (response-guided vs conventional: p=0.153; TACx6 vs TACx8: p=0.335; TACx6 vs TAC/NX: p=0.420). Similar negative results were found for HR+ and HR- subgroups. Conclusions: Pre-CT Ki-67 levels are predictive for pCR and prognostic for DFS. Post-CT Ki-67 levels and changes between pre-and post-CT-Ki-67 levels are prognostic for DFS. As neither could predict different treatment effects on DFS, Ki67 cannot replace pCR as a surrogate marker for outcome after neo-adjuvant CT.
Efficacy, safety, tolerability, and PK of the HDAC inhibitor resminostat in sorafenib-refractory hepatocellular carcinoma (HCC): Phase II SHELTER study.
2012-05-20

4115 Background: Resminostat (R), an oral HDAC inhibitor, was studied in the SHELTER trial evaluating safety, PK and efficacy in HCC patients (pts) refractory to sorafenib (S). R was explored as monotherapy and within a novel resensitization approach to overcome tolerance to S by the combination of both drugs. Methods: Pts with advanced HCC (BCLC B/C) were included in a multi-center, two-arm trial. Radiologic progression under S firstline therapy had to be confirmed by central review (RECIST) prior to study entry. A dose escalation of R (range 200 to 600 mg) combined with S (400 or 800 mg) was performed. Arm A investigated the drug combination (R+S), Arm B the monotherapy of R (600 mg). Primary objective was the progression-free survival rate (PFSR) after 12 weeks (w). Secondary objectives included safety, tolerability, tumor response, PFS, TTP, OS and the analyses of PK and biomarkers (BM), incl. AFP, VEGF, HDAC enzyme inhibition, histone acetylation and gene expressions in peripheral blood. Results: 50 pts were enrolled, dose escalation determined 600 mg R and 400 mg S for Arm A. Clinical activity results of 15 evaluable pts from combination treatment revealing a PFSR of 66.6% after 12 w, not all patients in Arm B already reached the 12 w staging. Most frequent AE were CTC grade 1-2 GI complaints (nausea, vomiting) and skin disorders (rash, pruritus, HFSR). Grade 3-4 toxicity (SAE reports) consisted mainly of non-hematological events mostly related to tumor disease. Plasma concentrations of both drugs correlated with administered doses and were in the expected range without obvious influence of preexisting liver disease. BM investigations revealed effective target modulation by R in both arms. Conclusions: The primary study objective was achieved for both treatment arms. R demonstrated a favorable PK, safety and tolerability profile, even in combination with S and despite preexisting liver disease, includig cirrhosis. The observed clinical activity emphazises the resensitizing activity of R by an epigenetic mode-of-action to overcome tolerance to S and warrants further development, in particular for combination therapy in both, first and second line HCC treatment.
Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.
2012-05-20

8526 Background: Brain metastases are a major contributor to mortality in stage IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor progression and therapy resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib recently gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, ongoing clinical studies suggest short-lived responses to BRAF inhibitors in melanoma brain metastases. Methods: We observed in several melanoma patients that chemotherapeutics or BRAF inhibitors yielded a significant regression of extracerebral metastases while brain metastases progressed or newly occurred. We therefore aimed at identifying factors that may contribute to treatment resistance of brain metastases. Results: Immunohistochemistry of matched brain and extracerebral melanoma metastases demonstrated an identical pattern of ERK, p-ERK and AKT staining but a different pattern of p-AKT and PTEN staining with hyperactivation of AKT and loss of PTEN expression in brain metastases. Mutation analysis revealed no difference in BRAF, NRAS or KIT mutation status in matched brain and extracerebral metastases. By contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and PTEN was identical in cell lines derived from brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed hyperactivation of AKT compared to melanoma cells stimulated by fibroblast-conditioned medium. When inhibiting the MAPK and AKT signaling pathways at different levels in cells freshly isolated from melanoma brain metastases, growth inhibition and apoptosis induction was most pronounced with novel PI3K inhibitors such as BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation of the AKT survival pathway is brain environment-induced and relevant for the survival of melanoma cells in the brain parenchyma and that 2) inhibition of AKT signaling may be a suitable strategy to enhance and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors in melanoma brain metastases.
Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: Results from a phase III study.
2012-05-20

8512 Background: Ipilimumab (IPI), a fully human monoclonal antibody, blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. In a phase 3 study (CA184-024) of previously untreated pts with stage III or IV melanoma, IPI + dacarbazine (DTIC) significantly improved overall survival (OS) vs. DTIC alone (Robert et al. NEJM 2011). We now report safety data of IPI in pts from this study alive &gt; 2 yrs from study initiation. Methods: Pts with untreated advanced melanoma, were randomized to IPI (10 mg/kg) + DTIC (850 mg/m 2 ) or placebo + DTIC (850 mg/m 2 ) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Eligible pts (stable disease or better) received IPI or placebo q 12 wks as maintenance. In the population of subjects alive &gt;2 yrs, the appearance of immune-related adverse events (irAEs) occurring after 2 yrs was evaluated. Within this group was a subset of subjects still receiving IPI dosing after 2 yrs; safety for these pts was evaluated to assess the impact of prolonged IPI exposure. Results: In the IPI + DTIC group 68 (28%) pts survived &gt; 2 yrs compared to 44 (18%) in the DTIC alone group; 11 of the 68 continued IPI dosing for ≥ 2 yrs. Safety assessment beyond 2 yrs showed 3 of the 11 pts had any grade irAEs; 1 pt had grade 3/4 rash, pruritus while low grade events included rash, pruritus (n=2) and elevated ALT / AST (n=1). Overall among all 68 pts in the Ipi + DTIC group, there were 5 pts (7.4%) with any grade irAEs including grade 3/4 rash, pruritus (n=1) and low grade rash (n=3), pruritus (n=2), skin hypopigmentation, and elevated ALT / AST (n=1). No gastrointestinal or endocrine events (any grade) were observed. Conclusions: In Study 024, IPI + DTIC treatment improved OS pts with untreated, advanced melanoma with higher survival rates in the IPI + DTIC group at 1 yr (47.3% vs. 36.3%), 2 yrs (28.5% vs. 17.9%), and 3 yrs (20.8% vs. 12.2%) (HR 0.72, p&lt;0.001). The safety profile of pts alive after 2 yrs suggests that treatment with IPI + DTIC is associated with low rates of irAEs in these pts. Furthermore, in pts still receiving active IPI treatment beyond ≥ 2 yrs, the safety profile appears to be consistent and medically manageable using established safety guidelines (Weber, Oncologist 2007).
Overall survival (OS) of advanced colorectal cancer (aCRC) patients (pts) treated with the multipeptide vaccine IMA910: Results of a matched-pair analysis with arm C pts from COIN.
2012-05-20

3530 Background: IMA910 is a novel cancer vaccine consisting of 10 class I and 3 class II tumor-associated peptides (TUMAPs), naturally presented on HLA molecules of CRC. Vaccine-induced immune responses are associated with prolonged OS of renal cell carcinoma pts treated with IMA901, a multi-peptide vaccine identified by the same antigen discovery platform. Methods: 92 HLA-A*02+ aCRC pts with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After immunomodulation with cyclophosphamide (300 mg/m 2 ) to reduce regulatory T cells, pts were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod. Safety and PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of IMA910 pts was compared to matched pts from arm C (intermittent chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011]. Matching was performed in a prospectively defined, fully blinded fashion based on a propensity score involving all available prognostic factors. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs, OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1 matched HLA-A*02+ COIN pts (HR 0.675, 95% CI 0.458-0.995, p=0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP responders (≥2 CD8+ and ≥2 CD4+ vaccine-induced T cells) had a significantly longer OS (HR 0.45, p=0.04) compared to matched COIN pts while non-multi-TUMAP responders showed similar OS compared to matched COIN pts (HR 0.76, p=0.22). Conclusions: OS of IMA910 pts was significantly longer in comparison to matched COIN pts with separation of survival curves at ~9 months and increasing OS difference over time. Multi-TUMAP immune responders had a significantly longer OS compared to non-multi-TUMAP responders and compared to matched COIN pts. These clinical and immune response data strongly suggest clinical activity of IMA910 in 1st line CRC pts and warrant further development.
Immune responses and association with clinical outcome of advanced colorectal cancer patients treated with the multi-peptide vaccine IMA910.
2012-05-20

2522 Background: IMA910 is a novel multi-peptide cancer vaccine consisting of 10 HLA class I and 3class II tumor-associated peptides (TUMAPs), which were selected based on natural presentation on colorectal tumors by the XPRESIDENT antigen discovery platform. Methods: 92 HLA-A*02+ advanced colorectal cancer (aCRC) patients (pts) with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After pre-treatment with cyclophosphamide (300 mg/m 2 ), patients were immunized intradermally with IMA910 plus the immune modulator GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod, another immune modulator acting via toll-like receptor 7 on antigen presenting cells. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine staining (ICS) assays. Results: IMA910 elicited immune responses towards multiple class I (43%) and class II TUMAPs (65%). 34% of pts responded to multiple class I and class II TUMAPs. Pts that received imiquimod were more often multi-peptide class I responders in the ICS assay (p=0.016) and showed an approx. 2x higher frequency of T-cell response (p=0.12). Responses to multiple class I and class II TUMAPs were associated with higher disease control rate at all time points (all p&lt;0.02), increased time to progression (p=0.006), progression-free survival (p=0.009) and OS (p=0.088, HR=0.53). Baseline characteristics of multi vs. non-multi responders were overall well comparable. In a prospectively defined, blinded matched-pair analysis with patients in arm C of the COIN trial, multi-peptide responder patients showed a prolonged survival vs. corresponding COIN patients (p=0.04), while the non-multi responder patients had comparable survival. Conclusions: IMA910 is immunogenic. Imiquimod increases the quality of immune responses. Responses to multiple TUMAPs are associated with better clinical outcome. Several observations indicate that this association is not a reflection of better prognosis of the immunologically responding subset of patients. These results suggest further development of IMA910.