bluuebunny/crossref_metadata_2025 huggingface dataset:
Patient-specific immunotherapy utilizing putative tumor stem cells in patients with metastatic melanoma: A pooled analysis comparing tumor cell and dendritic cell vaccines in two phase II trials and a randomized phase II trial.
Authors: Dillman Robert Owen , DePriest Carol , de Leon Cristina , Barth Neil M. , McClay Edward Francis , Amatruda Thomas , Schwartzberg Lee Steven , Sheehy Patrick Frank , Mahdavi Khosrow , Mayorga Cheryl Ann , Ellis Robin Anne
Published: March 2020

2569

Background: Metastatic melanoma is seldom cured, even in patients who achieve a complete remission, because new sites of disease emerge. Autologous, proliferating, self-renewing tumor cells (putative tumor stem cells and/or early progenitor cells), are critical to establishment of new depots of metastatic cancer, and may be excellent sources of antigen for vaccines. These trials addressed the impact on survival from immunizing with antigens from such cells. Methods: Data was pooled from 3 successive phase II trials, all of which included patients with documented metastatic melanoma, who were treated in protocols that utilized antigens from cell cultures of autologous tumor cells. S.C. injections were given weekly for 3 weeks, then monthly for 5 months. 1992-2000: 74 patients were injected with irradiated tumor cells (TC). 2000-2006: 54 patients were injected with autologous dendritic cells (DC) that had been co-cultured with irradiated autologous tumor cells (NCI-V01-1646). 2007-2011: in a randomized phase II trial, 24 patients were injected with TC, and 18 with DC (NCT00436930). Results: The table summarizes overall survival (OS) in each trial. In the pooled analysis there were 98 TC and 72 DC patients. Characteristics were similar in terms of age (51, 52), male gender (62%, 62%), no evidence of disease at the time of treatment (46%, 47%), and presence of M1c visceral disease at the time of treatment (13%, 14%). OS was longer in patients treated with DC (median 63.1 vs 20.2 months, 5-year OS 51% vs 26%, p=0.0002 Mantle-Cox log-rank test). The difference in OS in the randomized trial is also significant (p=0.007). Conclusions: Patient-specific DC vaccines primed with antigens from autologous proliferating, self-renewing tumor cells are associated with encouraging long-term survival rates, and are superior to patient-specific TC vaccines in populations of patients who have been diagnosed with metastatic melanoma. [Table: see text]
Adoptive cell therapy for melanoma patients using tumor-infiltrating lymphocytes, lymphodepleting chemotherapy, and low-dose interleukin-2.
Authors: Ellebaek Eva , Iversen Trine Zeeberg , Junker Niels , Donia Marco , Engell-Noerregaard Lotte , Andersen Mads Hald , thor Straten Per , Svane Inge Marie
Published: March 2020

2574

Background: Adoptive T cell therapy is based on isolation of tumor infiltrating lymphocytes (TIL) from autologous tumor, in vitro activation and expansion, and the reinfusion of these cells into a lymphodepleted patient. Together with high-dose interleukin (IL)-2 this treatment has in a few other countries successively been given to patients with advanced malignant melanoma and an impressive 50% response rate has been observed. Here we report the experience from a Danish Translational Research Center using low-dose subcutaneous IL-2 injections. Methods: A pilot trial including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease, and no CNS involvement. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of low-dose IL-2, 2 MIU/day. Results: Low-dose IL-2 considerably decreased the toxicity of the treatment with no grade 3-4 events related to this drug. Two of the 6 treated patients have an ongoing complete response (30+ and 7+ months), 2 patients had stable disease (4.5 and 5 months) and 2 patients progressed shortly after treatment. Five patients went through surgery but were not treated because of rapid disease progression (2), development of brain metastases (2) or the inability to grow cells (1). Tumor-reactivity of the infused cells and peripheral monocytes before and after therapy were analyzed. High tumor responses in the infusion products were correlated to clinical response and also an induction of tumor reactive T cells were seen in the peripheral blood for 1 patient in complete response. Conclusions: Complete and durable responses are induced after treatment with adoptive cell transfer in combination with low-dose IL-2 questioning the need for high and toxic doses of IL-2.
An alternative clinical trial design for early cancer vaccine development to phase 3+3 design.
Authors: Gammoh Emily , Rahma Osama E. , Simon Richard , Khleif Samir
Published: March 2020

2578

Background: Traditional phase I, “3+3 dose escalation” design, is conducted to identify the MTD and in some cases the optimal biologic dose. Given their unique mechanism of action and the profile of their clinical outcome, this design may not apply to cancer vaccines. The therapeutic cancer vaccine FDA guidance calls for an alternative early development design. Nevertheless, whether an alternative design should be based on “dose escalation” is still an opened question. Methods: We analyzed the toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 vaccine related systemic toxicities were reported in 4952 treated patients (1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used dose escalation reported vaccine related DLTs, both trials used bacterial vectors. Furthermore, correlation of immunological response with dose level showed no consistent trend. Conclusions: Our analysis suggests that in cancer vaccines neither toxicity nor cellular immune response correlates with dose levels. Accordingly, dose escalation is not suitable for most cancer vaccine studies. Here, we propose a two-step alternative design for early development of cancer vaccines. The first step is to determine and confirm the minimum Immune-Active Dose (IAD). If a vaccine class has been used in humans, IAD dose is chosen based on previous experience if the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation will be used. For a vaccine class that has not been tested or has undetermined toxicity we recommend “One Patient Escalation Design” (OPSD): one patient is treated per tested dose until an immune response is induced. To confirm this activity, an expanded cohort of 7 patients will be tested until demonstrating an additional response. This will then be used in phase II combination therapy trial. Alternatively, IAD can be directly tested in combination with an immune modulator in a phase II clinical trial using a two-stage design. The first stage of the phase 2 trial can be set at 4-5 patients for a target response rate of over 50%. If no response is seen, then the immune modulator will be escalated in the second stage.
Association of humoral antitumor response with clinical benefit in catumaxomab-treated malignant ascites patients: Results from a phase IIIb study.
Authors: Ruf Peter , Suckstorff Ivonne , Jäger Michael , Ernst Christine , Seimetz Diane , Lindhofer Horst
Published: March 2020

2584

Background: The bispecific antibody catumaxomab (anti-EpCAM x anti-CD3) which is approved for the treatment of malignant ascites (MA) patients (pts) in the EU elicits a humoral immune response against tumor-associated antigens. Here we present follow up data analyzing the influence of this antibody response on puncture free (PFS) and overall survival (OS). Methods: In the course of the phase IIIb study CASIMAS, MA pts with EpCAM positive tumors were treated with/without prednisolone premedication by 4 infusions of 10, 20, 50 and 150 µg of catumaxomab over 11 days (d). EpCAM and HER2-specific antibody responses in plasma samples of 23 pts were measured by ELISA. Additionally, samples of 5 pts receiving a second treatment cycle were analyzed. Pts with significant increase (≥ 2) or de novo development of anti-tumor antibodies within 38 d after treatment start were defined as responders (R). Non responders (NR) showed no humoral response by d 38 or died before. PFS and OS of R and NR were compared by Kaplan Meier analysis. Results: 11 of 23 pts (48%) showed an anti-EpCAM response and 14 of 23 pts (61%) developed HER2-specific antibodies. 6 pts (26%) reacted positive against both antigens, 4 pts (17%) had neither response. In contrast to the EpCAM R group where 73% of pts displayed detectable antibodies prior to therapy, antibodies against HER2 developed de novo. Of note, 4 of 5 individuals who received a second treatment cycle after recurring MA demonstrated an anti-HER2 Ig booster reaction which was stronger and faster in comparison to pts who received only one treatment cycle (median values at d 18: 65 vs. 11 ng/ml). Most important, there was an almost 6 fold increase in median PFS between the HER2 R and NR group (68 vs 12 d, p = 0.044 (log-rank). There was also a trend towards improved OS for pts showing either anti-HER2 and/or anti-EpCAM responses (n=19) in comparison to pts with no response at all (n=4; 143 vs. 67 d, median, p = 0.054). Conclusions: The results indicate that active anti-tumor immunization triggered by catumaxomab treatment in MA pts is associated with improved clinical outcome. Further investigations of these vaccine-like effects with higher pts numbers are warranted.
Phase I/II study of resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with melanoma.
Authors: Sabado Rachel Lubong , Pavlick Anna C. , Gnjatic Sacha , Cruz Crystal M , Vengco Isabelita , Hasan Farah , Darvishian Farbod , Chiriboga Luis , Holman Rose Marie , Escalon Juliet , Muren Caroline , Escano Crystal , Yepes Ethel , Sharpe Dunbar , Adams Sylvia , Ott Patrick Alexander , Jungbluth Achim A , Pan Linda S. , Venhaus Ralph Rudolph , Bhardwaj Nina
Published: March 2020

2589

Background: The TLR 7/8 agonist, Resiquimod has been shown to induce local activation of immune cells, production of cytokines, and antigen-presentation by dendritic cells, features desirable for cancer vaccine adjuvants. In this study, we evaluated the safety and immunogenicity of vaccination with NY-ESO-1 protein emulsified in Montanide ISA-51 VG when given with or without Resiquimod in patients with surgically resected stage IIB-IV melanoma patients. Methods: This is a two-part study design. Part I represents an open-label dose-escalation with Resiquimod using 2 cohorts treated with 100ug NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by topical application of 1000mg of the 0.2% Resiquimod gel on days 1 and 3 for cohort-1 (N=3) or days 1, 3, and 5 for cohort-2 (N=3). The cycles were repeated every 3 weeks, total of 4 cycles. Part II of the study is blinded. Patients were randomized to receive 100ug NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by topical application of placebo gel (Arm-A; N=8) or 1000mg of 0.2% Resiquimod gel (Arm-B; N=12) using the dosing regimen established in Part I. Blood samples were collected at baseline, one week after each cycle of vaccination, and at follow-up visit for the assessment of NY-ESO-1-specific humoral and cellular immune responses. Results: Enrollment has been completed. 25/26 patients received all 4 vaccinations. The treatment was generally well-tolerated, with no grade 4 adverse events or study-related deaths. The most common toxicities were mild to moderate and included local injection site reactions (granuloma, pruritus, induration) and systemic flu-like symptoms. One patient experienced a grade 3 syncopal episode that was deemed unrelated to the drug. Another patient experienced a grade 3 injection site necrosis that was possibly related to the study drug and was removed from the study prior to receiving the 4th vaccine. Conclusions: This study demonstrates the safety of Resiquimod as an adjuvant for NY-ESO-1 protein vaccination. The study will remain blinded until all immune monitoring assays have been completed. An updated abstract will be submitted once the study is unblinded.
Individual PK-guided sunitinib dosing: A feasibility study in patients with advanced solid tumors.
Authors: Lankheet Nienke A.G. , Kloth Jacqueline S.L. , Gadellaa-van Hooijdonk Christa G.M. , Cirkel Geert A. , Mathijssen Ron H.J. , Lolkema Martijn P.J.K. , Schellens Jan H. M. , Voest Emile E. , Sleijfer Stefan , Beijnen Jos H. , Huitema Alwin D.R. , Steeghs Neeltje ,   Center for Personalized Cancer Treatment, Netherlands
Published: March 2020

2596

Background: Sunitinib treatment shows a clear dose-efficacy relationship. However, due to large inter-individual variations in plasma exposure, target total trough levels (> 50 ng/mL) are frequently not reached with the current dosing schedule. Therefore, a prospective Phase I study was performed to determine the safety and feasibility of PK-guided dosing of sunitinib. Methods: Thirty patients with solid tumors with a potential benefit from sunitinib treatment were included. Patients were treated continuously with sunitinib 37.5 mg once daily. At day 15 and 29 of sunitinib treatment, plasma trough levels of sunitinib and its active metabolite (N-desethyl sunitinib) were measured. If the total trough level (TTL) was < 50 ng/mL and the patient did not show any ≥ grade 3 toxicity (CTCAE 4.02), the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from ≥ grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg. After 8 weeks a final TTL evaluation was performed. Results: All 30 patients started treatment and in 18 patients all 3 TTLs were measured at the time of this analysis. Given TTL < 50 ng/mL and < grade 3 toxicity, a first sunitinib dose increase could be applied in 10 patients and a second dose increase in 2 patients at day 15 and 29, respectively. At day 15, day 29 and 8 weeks of treatment, mean TTLs were 49.7 ng/mL (coefficient of variation (CV) 27.7%), 62.4 ng/mL (CV 35.5%) and 56.7 ng/mL (CV 47.8%), respectively. At day 15, using the sunitinib standard dose of 37.5 mg, target TTLs were reached in 8 patients (44%). At 8 weeks, the mean sunitinib daily dose intensity was increased to 40.3 mg (standard deviation (SD) ± 11.0). At the end of the 8 week study period, 5 out of 18 patients (28%) were still at an increased sunitinib dose level without additional side effects. In these patients the mean daily sunitinib dose was 55.0 mg (SD ± 6.8) and their final TTLs were all > 50 ng/mL (mean: 70.8 ng/mL (CV 29.8%)). Using PK-guided sunitinib dosing, target TTLs were reached in 10 out of 18 patients (56%) at the final TTL evaluation, compared to 44% at day 15 before any dose adjustment. Conclusions: Individual PK guided dosing is feasible and enables a significant increase in sunitinib dose intensity without causing additional toxicity.
Effects of metformin and sulfonylureas on overall and colorectal cancer-specific mortality.
Authors: Spillane Susan , Bennett Kathleen , Sharp Linda , Barron Thomas Ian
Published: March 2020

2599

Background: Preclinical studies have suggested a role for metformin in the treatment of colorectal cancer (CRC). Associations between metformin versus sulfonylurea exposure and mortality (all-cause and colorectal cancer specific) are assessed in this population-based study of patients with a diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland records were linked to prescription claims data and used to identify a cohort of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From this cohort, 2 patient groups were identified and compared for outcomes - those who received a prescription for metformin +/- a sulfonylurea (MET) or a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models adjusted for age, sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin or statin exposure. Analyses were repeated stratifying by stage and site. Results: 5,617 patients with stage I-IV CRC were identified, of whom 369 received a prescription for metformin or a sulfonylurea in the 90 days pre diagnosis (median follow-up 1.6 years; MET: n=257; SUL: n=112). In adjusted analyses metformin exposure was associated with a 28% lower risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95% CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in colon cancer, metformin exposure was associated with a significant one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95) and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI 0.40-1.02). No mortality benefit was observed for rectal cancer. The association between metformin exposure and reduced mortality was strongest for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32-0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions: Pre-diagnosis metformin exposure in CRC patients was associated with a significant reduction in mortality relative to sulfonylurea exposure. This benefit was greatest in patients with colon cancer and early stage disease.
Impact of body surface area on efficacy of gefitinib in patients with non-small cell lung cancer harboring activating epidermal growth factor receptor mutation.
Authors: Ichihara Eiki , Hotta Katsuyuki , Hisamoto Akiko , Takigawa Nagio , Tabata Masahiro , Tanimoto Mitsune , Kiura Katsuyuki
Published: March 2020

2607

Background: Gefitinib is an essential drug for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. Its approved dosage is fixed at 250 mg/body/day without any adjustment by physical size. On the other hand, most cytotoxic agents are administered with body surface area (BSA) based dose-adjustment to reduce the pharmacokinetic inter-patient variability. However, the impact of BSA on efficacy of gefitinib has not been fully evaluated. We here tried to clarify this issue using our retrospective cohort. Methods: We reviewed the medical records of consecutive advanced NSCLC patients harboring EGFR mutation who underwent gefitinib monotherapy at Okayama University Hospital from October 2002, when gefitinib was approved in Japan, to October 2011. Results: A total of 101 patients with EGFR-mutant tumors who received gefitinib (250 mg/body/day) were included in this study. The median progression free survival (PFS) of patients with high BSA (≥1.5 m2: the median value in this cohort) was significantly worse than that of patients with low BSA (<1.5 m2) (10.4 vs. 18.0 months, p = 0.019 log-rank test). The multivariate analysis also showed a significant impact of BSA on PFS; (hazard ratio of 2.34 with 95% confidence interval of 1.78 - 2.89, p = 0.002). By contrast, such significant association between BSA and PFS was not observed in cytotoxic chemotherapy (5.4 months vs. 3.7 months, p = 0.49, log lank test). Conclusions: BSA affected PFS in the gefitinib monotherapy, potentially suggesting the need for appraisal of BSA-based dose adjustment even in this molecular-target therapy.
Phase I study of OPB51602, a small molecule inhibitor of STAT3 phosphorylation, in patients with refractory solid malignancies.
Authors: Goh Boon C. , Wong Andrea LA , Soo Ross A. , Kong Li-Ren , Zee Ying Kiat , Chuah Benjamin , Lee Soo-Chin , Mikami Tomomi , Yuasa Miyuki , Marban Patrick , Yong Wei-Peng , Lwin Thuya Win , Zhu Qian
Published: March 2020

3002

Background: STAT3 is constitutively activated by growth signaling pathways in many malignancies; in many cell lines inhibition of STAT3 leads to cell death. OPB51602 is a small molecule inhibitor of STAT3 phosphorylation (Tyr705) and activation. Methods: A phase I study of OPB51602 administered for 2 weeks every 3 weeks was initiated to determine the maximum tolerable dose (MTD), evaluate pharmacokinetics (PK), and assess pharmacodynamics effects on STAT3 in peripheral blood mononuclear cells (PBMCs). The starting dose was 2mg/day, and dose escalations to 5mg/d, 10mg/d, 20mg/d, were planned. Single dose PK was done on the first day of administration for 4 days. Dose escalation was based on the “3+3” design, MTD was defined as the dose with at least 2/6 dose limiting toxicities (DLTs) in the first cycle and toxicities were graded by NCICTCv4.0. Results: 32 patients (pt) were treated at doses of 2mg/d (n=7), 4mg/d (n=18), 5mg/d (n=7). The main toxicities observed included nausea/vomiting, diarrhea, peripheral neuropathy and fatigue. 5 mg/d was the MTD, where cycle 1 DLTs of grade 3 diarrhea/dehydration and hyponatremia occurred in 1 patient respectively. One pt developed grade 3 peripheral neuropathy at 4mg/d cohort. PK showed maximal drug levels 2-3 hours after administration, bi-exponential decay, with mean oral clearance of 316.5 +/- 638.9 L/h and long terminal mean half-life of 61.8 +/- 15.9 h on day 17. STAT3 phosphorylation in PBMCs assessed in 6 pts receiving 4mg/d was reduced from 67.4 +/- 17.4% at baseline to 53.0 +/- 18.1% (p=0.001) after administration on day 1. Interestingly, reduction in tumor metabolism by PET CT on day 15 was observed in 4/8 pts receiving 4mg/d. A pt with heavily pretreated adenocarcinoma of lung at 5mg/d dose had partial response; another pt with metastatic endometrial cancer at 4mg/d dose experienced stable disease for 6 cycles. Conclusions: OPB51602 has an MTD of 5mg/d on this schedule, demonstrates inhibition of STAT3 phosphorylation, and evidence of clinical activity. Further proof of concept studies of OPB51602 are warranted.
A first-in-human phase I study of the oral Notch inhibitor LY900009 in patients with advanced cancer.
Authors: Pant Shubham , Jones Suzanne Fields , Kurkjian Carla , Infante Jeffrey R. , Moore Kathleen N. , Burris Howard A. , McMeekin D. Scott , Kursar Jonathan D. , Zamek-Gliszczynski Maciej , Jones Emma , Yuen Eunice , Chan Edward Michael , Bendell Johanna C.
Published: March 2020

3008

Background: Notch signaling plays a critical role during stem cell self-renewal and is deregulated in multiple human cancers. The Notch pathway may be activated inappropriately by receptor mutation and overexpression as well as aberrant signals from the tumor microenvironment. LY900009 is a selective small-molecule inhibitor of gamma secretase, the enzyme that cleaves and thereby activates Notch receptors. Methods: Dose escalation was performed in cohorts of 3 patients (pts) using a modified continual reassessment method. LY900009 was taken orally thrice weekly (every MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and clinical endpoints were evaluated. Results: 22 patients received LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts), 15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment emergent adverse events possibly related to LY900009 across all grades included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%), anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients, respectively, treated at 60mg. The maximum tolerated dose (MTD) was tentatively identified at 30mg. After a single dose, mean Cmax increased from 4 to 158 ng/ml and mean AUC0-t(last) increased from 14 to 1160 ng-hr/ml. Both Cmax and AUC0-t(last) increased in a dose-dependent manner. Elimination half-life of LY900009 was approximately 2-3 hrs. LY900009 inhibited plasma levels of amyloid-β peptide (a downstream product of gamma secretase) in a dose-dependent manner with 80-90% inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one patient had colonic biopsy that showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. Two patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles of therapy. Conclusions: LY900009 demonstrates acceptable safety and pharmacokinetics in patients with advanced cancer. Pharmacodynamic endpoints show pathway inhibition at tolerable doses. One more cohort at 45mg is ongoing to refine the MTD and will be followed by an expansion cohort for patients with ovarian cancer.
A phase I and pharmacokinetic (PK) study of continuous daily administration of P1446A-05, a potent and specific oral Cdk4 inhibitor.
Authors: Hao Desiree , Chu Quincy , Welch Stephen , Yau Cindy Y. F. , Spratlin Jennifer L. , Tang Patricia , MacKenzie Mary J. , Townsley Carol A. , Arndt Diane , Johnson Laureen , Trapsa Daniela , Degendorfer Pamela , Kulkarni Sujay , Jawlekar Gajendra , Dhobe Poornima , Oza Amit M.
Published: March 2020

3013

Background: P1446A-05 is a novel oral inhibitor of Cdk4-D1, Cdk1-B, and Cdk9-T, and has been shown to inhibit tumor growth both in vitro and in vivo. Pharmacodynamic studies demonstrate that activation of Cdk1 reappears within 48 hours after P1446A-05 is withdrawn, suggesting the need for prolonged administration hence, we sought to evaluate the feasibility, safety and tolerability of a continuous daily schedule of P1446A-05 in patients (pts) with advanced malignancies. Methods: P1446A-05 was given at escalating doses of 75, 150, 250, 350 and 500mg. Samples were collected for PK at multiple time points over 24 hours on cycle 1 day 1 and 15, as well as at single time points on cycle 1 day 8, 22 and cycle 2 day 1. Results: Thirty-nine pts (median age=63 years, 51% male, 51% ECOG PS=1) collectively received more than 100 cycles of P1446A-05. The majority of drug-related toxicities were ≤Grade 2, the most common of which were diarrhea (n=54), nausea/vomiting (n=27/17), fatigue (n=22) and anorexia (n=16). Two pts developed study-drug related diarrhea with hypokalemia/elevated creatinine and died during cycle 1. Dose-limiting toxicities (DLT) at 500mg (Table) led to subsequent de-escalation and expansion of the 350mg cohort. A total of 24 pts were treated at 350mg; only one patient experienced dose-limiting diarrhea. PK data are summarized below. Accumulation ratios across dose levels suggest moderate accumulation with continuous dosing. Nine pts achieved stable disease (SD) for at least 2 cycles. One pt with alveolar soft tissue sarcoma, whose disease was progressing at enrollment, remains on treatment with SD after 11 cycles. Conclusions: The recommend phase II dose of P1446A-05 is 350mg. Further phase II studies at this dose will be conducted with potential enrichment strategies. [Table: see text]
PX-866 and docetaxel in patients with advanced solid tumors.
Authors: Jimeno Antonio , Senzer Neil N. , Rudin Charles M. , Ma Wen Wee , Halmos Balazs , Schnadig Ian D. , Levy Benjamin , Hausman Diana Felice , Peterson Scott , Walker Luke N.
Published: March 2020

3024

Background: PX-866, an irreversible pan-isoform inhibitor of Class 1 PI-3K has additive to synergistic effects when combined with docetaxel in xenograft models of NSCLC and SCCHN. A phase I/II study of PX-866 and docetaxel was initiated to further evaluate this combination. Enrollment in phase I is complete, and the randomized, controlled phase II portion is now enrolling patients with either NSCLC or SCCHN. Phase I safety and pharmacokinetics were previously described; the recommended phase II dose of PX-866 was 8 mg daily, the same as the single agent MTD (Jimeno A, et al. AACR-NCI-EORTC, 2011). Updated phase I antitumor and biomarker results are presented here. Methods: Phase 1 consisted of dose escalation of PX-866 at 4, 6, or 8 mg po qd in combination with docetaxel 75 mg/m2 IV once every 21 days (d). Patients had advanced solid tumors for which docetaxel was compendia listed. Tumor restaging was performed every 2 cycles. Archived tumor biopsies were collected for assessment of potential biomarkers of response, including PIK3CA and KRAS mutations and PTEN expression. Results: 43 pts were enrolled: NSCLC (n=6), prostate (n=5), ovarian (n=5), SCCHN (n=3), and pancreatic (n=3) were the most common tumor types. Median time on study (TOS) was 81 d (5-361), with 9 pts still on study. 16 pts received ≥ 6 cycles (6-17), including 3 pts with NSCLC, and 4 pts with ovarian cancer. Biomarker data are available for 20 evaluable pts. Median days on study by mutational status was: PIK3CA/KRAS WT (n=13): 91 d (28-286); PIK3CA-MUT (n=5): 183 d (64-342); KRAS-MUT (n=3): 141 d (125-361); and PIK3CA/KRAS-MUT (n=2): 96 d (86-105). A trend toward longer TOS was observed in pts with PIK3CA-MUT vs PIK3CA/KRAS-WT (p=0.14). Assessment of PTEN is ongoing. Best response in 32 evaluable pts was 2 PR (6%), 22 SD (69%), and 8 PD (25%). The PRs were in NSCLC and ovarian cancer (both PIK3CA/KRAS WT). 8 other pts had ≥15% tumor shrinkage, including NSCLC (n=2). Conclusions: PX-866 with docetaxel was associated with a disease control rate of 75%, with 50% of evaluable pts demonstrating SD or better for ≥ 6 cycles. Based on available data, a trend for a longer TOS was seen with PIK3CA-MUT pts. This relationship will be further evaluated in phase II.
NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 targeted agent.
Authors: Thompson Dana Shelton , Weiss Glen J. , Jones Suzanne Fields , Burris Howard A. , Ramanathan Ramesh K. , Infante Jeffrey R. , Bendell Johanna C. , Ogden Angela , Von Hoff Daniel D.
Published: March 2020

3033

Background: NKP-1339 is a first-in-class small molecule anti-cancer compound that down-regulates GRP78, a key regulator of misfolded protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation occurs in many tumors, and is associated with intrinsic and chemotherapy-induced resistance. Preclinically, single agent NKP-1339 demonstrates activity against multiple tumor types, including chemoresistant lines. This phase I trial evaluates the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339. Methods: Patients (pts) with advanced solid tumors, adequate organ function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15 of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then adjusted to standard 3+3 design. Doses from 20-780 mg/m2 are evaluated. PD samples for plasma GRP78 are collected. At MTD, an expanded cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation: 30 evaluable for dose determination; 4 replaced due to tumor progression in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79). Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8); neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8). Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt, occurred at 780 mg/m2; MTD is 625 mg/m2. Gr 1 fever/chills is observed above 420 mg/m2, but is prevented by steroid premedication. The most common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2 fatigue. No lab abnormalities were noted except reversible creatinine elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial response was in 1 pt (NET); stable disease in 7 pts, including NET (2), NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy duration 14+-88+ weeks. Soluble GRP78 is detected in the plasma of patients at baseline. Conclusions: NKP-1339is well tolerated with manageable side effects. Single agent activity is noted in multiple tumors including NET. Results from the expanded cohort and pre/post-therapy PD will be presented. Phase II single agent NKP-1339 and phase I NKP-1339 combination trials are planned.
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR: Dose-escalation phase I study.
Authors: Kollmannsberger Christian K. , Hurwitz Herbert , Cleary James M. , Strickler John H. , Drouin Michel A. , Juretic Manuela , Hunt Wendy , Reid Gregory K. , Maroun Christiane R. , Bonfils Claire , Wang James , Karam Andre , Besterman Jeffrey M. , Mehran Mariam , Shapiro Geoffrey
Published: March 2020

3039

Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer greater anti-tumor activity than inhibiting either target alone. MGCD265 has broad anti-tumor effects in preclinical models. Methods: Patients (pts) with advanced malignancies were enrolled in this Phase I, open-label, dose escalating study using the classic 3+3 study design. MGCD265 was administered every day over a 21-day cycle. The aim of this study is to determine the safety profile including the maximum tolerated dose and the dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 were also evaluated. Results: As of January 10, 2012, 56 patients were enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a favorable safety profile. The DLTs (n=1 for each event) captured were: grade 2 hypertension (per protocol’s definition), grade 3 lipase elevation, grade 3 fatigue and grade 3 pituitary hemorrhage, all occurring at daily doses ≥ 250 mg/m2. Additional ≥ grade 3 drug-related adverse events (observed beyond Cycle 1) were diarrhea, fatigue, elevated lipase and elevated alkaline phosphatase (n=1 for each event). Two schedules of MGCD265 were tested sequentially: once (QD) and twice daily (BID), respectively. Increasing the dose frequency to BID increased the exposure of MGCD265 by ~ 2 fold at steady state. To date, the exposure (Cmax) attained at steady state with the BID schedule was ~20 fold higher than the IC50 for Met and VEGFR inhibition and was also above the plasma exposures associated with efficacy in the Met-sensitive xenograft model (MKN45). Six patients achieved SD for 6 cycles or more (up to 12 cycles). Conclusions: The safety profile of MGCD265 continues to be favorable in this Phase I dose escalating study. While no evidence of objective responses have been noted to date, several pts have had prolonged SD. Dose escalation is ongoing.
Clinical and correlative science results in a phase II study of UCN-01in combination with irinotecan in recurrent triple-negative breast cancer (TNBC).
Authors: Ma Cynthia X. , Ellis Matthew J. , Petroni Gina R. , Lockhart A. Craig , Naughton Michael , Pluard Timothy J. , Brenin Christiana , Picus Joel , Creekmore Allison N , Mwandoro Tibu N. , Guo Zhanfang , Cai Shirong , Ryan Christine , Yarde Erin , Hoog Jeremy , Dancey Janet , Watson Mark , Piwnica-Worms Helen , Fracasso Paula M.
Published: March 2020

3047

Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing “mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan (I) combined with UCN-01, a nonselective Chk1 inhibitor, showed promising activity in TNBC in our phase I study. The primary objective of the phase II trial was to determine the efficacy and toxicity. Correlatives included assessing tumor molecular subtype, TP53, PTEN and pathways targeted by UCN-01. Methods: Pts with measurable, metastatic (met) TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV on d2 and 35 mg/m2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial peripheral blood mononuclear cells (PBMC) and optional tumor biopsies were collected. Results: Twenty five pts were enrolled. All had prior A and T. The median no. of prior regimens for met disease was 3 (range 1-4). Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia. Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a clinical benefit rate (CR+PR+SD>6 mos) of 3/25 (12%), 95% CI (3, 31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6 was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC 24h post UCN-01, but close to baseline by d8. Immunostain of cleaved caspase 3 (CC3), pHistone H3 (pHH3), γH2AX, and pS6 were done on serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6 was reduced 24h post UCN-01. Results for other markers were variable. One case with TP53 deletion showed an induction of CC3, with an increase in pHH3 and γH2AX, suggesting abrogation of cell cycle arrest and enhanced DNA damage. Among 15 with sufficient specimen for analysis, most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2) by PAM50, low in PTEN level (11) and carried mutations in TP53 (8). Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95% CI: 2.9, - ) mos in wild type populations (p=0.004). Conclusions: This regimen had limited activity in TNBC. Despite the long half-life, drug activity is not detectable by d8 based on PBMC analysis. Our data indicates that future trials in TNBC should consider p53 status.
Developing rational drug combination strategies for PARP inhibitors.
Authors: Rehman Farah , Elliott Richard , Brough Rachel , Frankum Jessica , Ragab Anan , Lord Christopher J. , Ashworth Alan
Published: March 2020

3050

Background: The recent clinical development of Poly (ADP-ribose) polymerase (PARP) inhibitors has provided formal proof-of-concept that synthetic lethal approaches can be used to treat cancer. The promise of PARP inhibitors in BRCA mutant tumours is apparent but questions regarding their wider clinical use remain. To date, a number of clinical trials have been designed using PARP inhibitors as single agents as well as in combination with current standards of care. However, there is a paucity of pre-clinical information about PARP inhibitor/drug combinations and empirical clinical trials of standard of care plus PARP inhibitors may not represent the most effective approach to dissect this. We aim to identify effective drug combination strategies that could be used clinically in selected patient groups. Methods: Using a combination of high and medium throughput techniques and established methodologies for determining synergy, additivity and antagonism, we have characterised the effects of combining PARP inhibitors with a diverse panel of over 3,000 compounds in a range of tumour cell models including isogenic matched cell line pairs to determine the impact of genetic background on drug combination efficacy. We have integrated this data with functional profiling data to identify genetic backgrounds where these combinations may be most effective. Results: Results to date suggest promising combinations of PARP inhibitors with temozolomide, CHK1 inhibitors, ATM inhibitors and other agents. Some of these combinations show specificity for genetic backgrounds such as PTEN mutations. Conclusions: Screening of drug libraries has identified promising PARP inhibitor drug combinations and demonstrates how some drug combinations show specificity in particular genetic backgrounds. This raises the possibility of widening the therapeutic index in patients with these genetic backgrounds and treating a wider group of patients with PARP inhibitors.
Using proton MRSI to predict response to vorinostat treatment in recurrent GBM.
Authors: Shim Hyunsuk , Voloschin Alfredo Daniel , Wei Li , Hwang Scott N , Miller Andrew H. , Guo Ying , Brat Daniel , Holder Chad A , Read William L. , Kopcewicz Katarzyna , Harvey R. Donald , Barker Peter , Shu Hui-Kuo George , Hu Xioaping P , Olson Jeffrey J.
Published: March 2020

3055

Background: A major impediment to the development of new therapies for glioblastoma (GBM) is a lack of biomarkers indicating response. Epigenetic modifications are now recognized as a frequent occurrence in the early phases of tumorigenesis, playing a central role in tumor development. Epigenetic alterations differ significantly from genetic modifications in that they may be reversed by ‘‘epigenetic drugs’’ such as histone deacetylase inhibitors (HDACis). As a promising new modality for cancer therapy, the first generation of HDACi is currently being tested in phase I/II clinical trials. Methods: GBM alterations from therapy with HDACis, such as vorinostat (SAHA), include tumor redifferentiation/cytostasis rather than tumor size reduction limits the utility of traditional imaging methods such as MRI. Magnetic resonance spectroscopic imaging (MRSI) quantitates various metabolite levels in tumor and normal brain, allowing characterization of metabolic processes in live tissue. Results: In our preclinical model, MRS detected metabolic response to SAHA after only 3 days of treatment: reduced alanine and lactate and elevated myo-inositol, N-acetyl aspartate and creatine; each returning toward normal brain levels. This led to our clinical study of MRSI to evaluate the metabolic response of recurrent GBMs to SAHA + temozolomide. After only 7 days of SAHA treatment, MRSI can distinguish metabolic responders (normalization/restoration of tumor metabolites towards normal brain-like metabolism) from non-responders (no significant change in tumor metabolites). Our initial cohort (n=6) consists of 3 responders and 3 non-responders with highly significant differences in their change in metabolite levels (p < 0.001). Conclusions: Our results provide exciting insights into the mechanisms by which HDACi exerts its effect on GBMs. Tumor cells have increased biosynthetic needs requiring reprogramming of cellular metabolism. This creates increased energy demands, making tumor cells even more vulnerable to interventions targeting their metabolism. HDACi may induce redifferentiation in tumors by targeting tumor metabolism. Thus, MRSI provides a novel modality to predict response to HDACi-containing combination therapy in GBM.
A phase I/II study to evaluate the ability of decitabine and panobinostat to improve temozolomide chemosensitivity in metastatic melanoma.
Authors: Xia Chang , Laux Douglas Earl , Deutsch Jeremy Michael , Frees Melanie , Smith Brian , Hohl Raymond J. , Milhem Mohammed M.
Published: March 2020

3056

Background: Epigenetic gene regulation is likely a contributing mechanism of cancer initiation and progression. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. We proposed combining the histone deacetylase inhibitor panobinostat (PT) and the demethylator decitabine (D) to overcome the development of epigenetic mediated temozolomide (TMZ) resistance in metastatic melanoma. Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG ≤ 2) and normal organ functions. Patients with previous exposure to TMZ were allowed on study. The study includes the dose escalation of D and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle. TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the D, PT and TMZ combination. Results: To date, the phase I portion of this trial is completed. We report on the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only grade (G) 4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukopenia (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%). Conclusions: The combination of D, PT, and TMZ appears to be safe and well-tolerated. The recommended dose for the phase II study remains to be determined.
A phase I study of EP-100, a luteinizing hormone releasing hormone (LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with advanced refractory LHRH- receptor (R)-expressing tumors.
Authors: Ramanathan Ramesh K. , Chadha Manpreet , Sarantopoulos John , Northfelt Donald W. , Weiss Glen J. , Mita Monica M. , Barnhart Kerry M. , Whisnant John , Leuschner Carola , Alila Hector , Curtis Kelly Kevelin
Published: March 2020

3060

Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.