bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I trial of alvespimycin (KOS-1022; 17-DMAG) and trastuzumab (T)
Authors: Miller K. , Rosen L. S. , Modi S. , Schneider B. , Roy J. , Chap L. , Paulsen M. , Kersey K. , Hannah A. , Hudis C.
Published: March 2020

1115

Background: Alvespimycin (A) inhibits the activity of Hsp90, resulting in degradation of client proteins, such as the HER2 receptor. In vivo, Hsp90 inhibition induces rapid degradation of HER2 with loss of pAKT, cyclin D2 and tumor growth inhibition. Methods: Pts receive standard weekly doses of T followed by A in escalating doses via IV doses over 1 hr. Define the recommended dose (RP2D), toxicity and signs of activity of T+A in pts with solid tumors. PK: assessed after the 1st and 4th infusion. PBLs: purified to investigate changes in intracellular signaling proteins by immunoblot. The RP2D will produce DLT in no more than 1/6 evaluable pts. Results: 21 pts enrolled in 3 cohorts (60, 80 and 100 mg/m2). Median age 53 yrs, range 31–75; median KPS 90; prior regimens not including hormonal therapy: median 6, range 1–13; prior T-regimens for MBC pts: median 3, range 0–9. Diagnoses: HER2+ MBC (n=18), ovarian (n=3). DLT was observed at the highest dose, consisting of 1 pt with hypoxia and ↓LVEF; an additional pt at this dose had Grade 3 ↑AST, however ↑hepatic metastases and ascites were observed. Drug-related toxicity: diarrhea (60%), fatigue, headache (both 45%), nausea, arthralgias (both 40%), dry eye and pain in extremity (both 25%); all Grade 1–2 severity except 1 episode of Gr3 fatigue and Gr3 diarrhea. PK (n=18): t½ 17.7 hr (32%CV); Clearance 18.1 L/hr (46%CV); Vz 438L (42%CV); no change upon weekly dosing. AUCinf/Cmax (100 mg/m2): 14268 ng*hr/mL (60%CV) and 2233 ng/mL (23.5%CV). HER2+ MBC activity: 1 pt (13 prior regimens; 3x T and 1x lapatanib) with evaluable disease showed near complete resolution of lung metastases by CT/PET with significant improvement in dyspnea; 3 pts with HER2+ MBC with SD (4, 5 and 7+ months). Ovarian CA activity: 1 pt (HER2 unknown; 13 prior regimens; 11+ months on-study) with evaluable disease showed near complete resolution of ascites and pleural effusion at end of Cycle 2 with ↓83% CA125. Dose-dependent increase in Hsp70 in PBLs; at 80 and 100 mg/m2, Hsp70 induction was maintained prior to successive weekly doses. Conclusions: Combination of T+A has signs of activity in H-refractory HER2+ MBC and refractory ovarian cancer. Definition of RP2D dose is pending. Toxicity has been manageable.

No significant financial relationships to disclose.
Phase 2 study of MKC-1 in patients (pts) with metastatic breast cancer (MBC) who have failed prior therapy with an anthracycline (A) and taxane (T)
Authors: Sylvester L. , Laufman L. , Jabboury K. , Saleh M. , Tkaczuk K. , Volterra F. , Arnott J. , Hannah A. , Sidor C. , Miller K.
Published: March 2020

11508

Background: MKC-1 (previously Ro 31–7453) is a novel cell cycle inhibitor with significant in vitro and in vivo activity against a wide range of tumor cell lines, including multi-drug resistant cell lines. Proteins identified as binding targets of MKC-1 include microtubules (colchicine binding site) and members of the importin-β family (proteins that play a critical role in nuclear transport and spindle formation). Objective responses (ORs) were observed in heavily pre-treated breast and NSCLC pts (Trigo Perez ASCO’03 A62; Kurup ASCO’03 A2725) treated at a dose of 95 mg/m2 BID given 14 days every 4 weeks with little toxicity. Salazar et al (2004 CCR 10:4374) recommended a higher oral dose (125 mg/m2 BID) on this schedule for further studies. This phase 2 trial is exploring the higher dose to maximize potential anticancer activity. Methods: Pts with MBC who had failed prior A and T and met eligibility criteria received MKC-1 at 125mg/m2 BID x 14d every 4 weeks. Pts with known treated and stable CNS metastases could enroll. Primary objective: OR by RECIST. Should 2 or more of the first 23 evaluable pts have an OR, enrollment will continue to 53 pts. Dose escalation/reductions are required based on toxicity (primarily neutropenia). Results: To date, a total of 20 pts have been enrolled (4 active in Cycles 1–5+). All female; median age/KPS of 60/90. 19% / 13% had received A / T in the neo/adjuvant setting; others had received A / T for metastatic disease. To date, a total of 48 cycles (median 2, range 1–8) were administered; of pts proceeding into Cycle 2, 40% and 20% had the dose increased or reduced, respectively. Severe drug-related toxicity (n=17) was observed in 3 pts (18%): ↑AST/ALT in 2 pts and parathesias in 1 pt. Drug related toxicity: nausea (47%), ↑ALT, diarrhea (both 24%), anemia, ↑AST, cough, fatigue, neutropenia and vomiting (all 18%). Two pts discontinued due to toxicity. One pt had complete resolution of measurable disease (1st observed after Cycle 4, confirmed after Cycle 6 with withdrawal for a new lesion at Cycle 8). An additional 2 pts had stable disease for 5 cycles (1 pt remains active). Conclusions: MKC-1 is well tolerated at the initial recommended dose for this schedule. Activity is observed in pts previously treated with A/T for MBC.

No significant financial relationships to disclose.
Does the addition of COX-2 inhibitors alter the resistance to aromatase inhibitors?
Authors: Gemici C. , Salepci T. , Bese N. , Gocen E. , Yaprak G. , Mayadagli A.
Published: March 2020

11511

Background: This study aimed to investigate whether the addition of COX-2 inhibitor to aromatase inhibitor alter the resistance to aromatase inhibitor, developed during first or second line hormonal treatment of estrogen (ER) and/or progesterone receptor (PR) positive metastatic breast cancer cases. Methods: ER and/or PR positive breast cancer patients with known high baseline CA 15–3 levels due to the tumor and receiving a first or second line (after first line tamoxifen) aromatase inhibitor due to soft tissue (lymphatic tissue, skin) or bone metastasis were evaluated in this study. A recurrent increase in CA 15–3 levels without tumor progression following an initial decrease in CA 15–3 levels was observed in 7 patients and this was considered as resistance to the aromatase inhibitor. For this reason, a COX- 2 inhibitor was added to either letrozole (5/7) or anastrozole (2/7) treatment. The aromatase inhibitor and COX-2 inhibitor combination (celecoxib 200 mg bid, 5/7 cases; rofecoxib 50 mg od, 2/7 cases) was used for 3 months. CA 15–3 levels and tumor response of these 7 cases was re- evaluated at the end of 3 months. Results: None of the seven cases had a decrease in CA 15–3 levels following the 3 months of aromatase inhibitor plus COX-2 inhibitor combination treatment, instead all cases had their levels increased. In addition, none of the 7 cases had clinical or radiological tumor response, all had tumor progression. Treatment was continued by either third line hormone treatment (4/7) or chemotherapy (3/7). Conclusions: COX-2 inhibitors are suggested to potentiate endocrine treatment since the overexpression of COX-2 contributes to the increased expression of aromatase in the breast tumor tissue. Thus, the combination of an aromatase inhibitor and a COX-2 inhibitor may be useful in the hormonal treatment of breast cancer. However, present study failed to demonstrate alteration of the developed aromatase resistance by the addition of a COX-2 inhibitor.

No significant financial relationships to disclose.
The role of HER2/neu, estrogen, and progesterone receptor status in the risk and survival of breast cancer leptomeningeal metastasis
Authors: Grewal J. , Groves M. D. , Bekele B. N. , Yung W. A.
Published: March 2020

11512

Background: Leptomeningeal metastasis (LM) is a dreaded complication of breast cancer with a median survival of approximately 4 months from the time of LM diagnosis. HER2/neu (HER2), estrogen (ER), and progesterone (PR) receptor status are routinely used to determine prognosis and guide treatment. There is emerging data regarding the influence of these receptors on the risk and prognosis of parenchymal brain metastasis. However, the role of these receptors in LM is unknown. We performed a retrospective analysis of 61 patients with breast cancer to determine the risk and survival of LM as a function of receptor status. Methods: Of patients with breast cancer evaluated in our department for possible LM between 2003 and 2006, those requiring CSF analysis were included in this study. Of these 61 patients, 27 were diagnosed with LM and 34 were found to be negative for LM, based on analysis of CSF and MRI. Information regarding HER2 receptor status was unavailable in 3 patients (1 with LM) due to technical issues with the assay. ER, PR, and survival data were available for all patients. Odds ratio of developing LM was calculated based on each receptor status. The Fisher exact test was used to determine significance. For the 27 patients with LM, receptor status was used to stratify survival from the time of LM diagnosis using Kaplan-Meyer analysis; significance was evaluated using the log-rank test. Results: The odds ratios of developing LM in patients with positive HER2, ER, and PR were 1.89, 0.32, and 0. 825, respectively. P values were 0.378, 0.056, and 0.799. In the 27 patients with LM, survival from the time of LM diagnosis was not significantly different when stratified by receptor status; p values were 0.983, 0.317, and 0.625 respectively. Conclusions: Our retrospective analysis suggests that HER2/neu-positive and ER-negative breast cancer may be associated with a higher risk of LM, although this approached statistical significance only for ER. For patients with confirmed LM, there were no significant differences in survival based on receptor status, although there was a trend favoring ER-positive disease. Larger studies are needed to clarify the role of these receptors in the risk and prognosis of breast cancer LM.

No significant financial relationships to disclose.
Variation in prognostic factors in hormone receptor-positive breast cancer patients who responded to hormonal therapy and those who did not: A retrospective analysis
Authors: Jain A. , Bapsy P. , Attili S. V. , Batra U. , Dasappa L. , Govindbabu K. , Sajeevan K. , Saini K. V. , G A.
Published: March 2020

11514

Background: Hormone receptor positive patents historically had a better prognosis than their receptor negative counterparts when other parameters are balanced. However not all the patients expressing Estrogen and progesterone respond well to the hormonal manipulation. Therefore we thought of doing a retrospective analysis of our hospital data to find out the differences in the prognostic factors in therapy responders and non responders. Methods: The study was conducted at tertiary care cancer center from India. Between 2002–2003 a total of 120 breast cancer patients who expressed either Estrogen receptor (ER) or progesterone receptor (PR) were analyzed. Only patients with metastatic breast cancer were analyzed. The patients were treated with our standard institutional protocol at the beginning according to the stage of the disease. The details and baseline characters were shown in table . Results: The responders tend to be post menopausal, having low grade, node negative tumors, expressed both ER and PR, and had long interval from the date of initial diagnosis. However tumor size and the site of metastasis (visceral vs. non visceral) did not alter the outcome to hormone therapy. Conclusion: patients who are having higher age, lower tumor grade, lower number of nodes, longer disease free interval after adjuvant therapy and expressing both receptors tend to respond to hormone therapy better than those who had the opposite characters. However as thought earlier, presence of visceral metastasis or larger tumors at the time of initial diagnosis dose not preclude response to hormonal manipulation.

[Table: see text]

No significant financial relationships to disclose.
Tinzaparin prophylaxis in brain tumor patients
Authors: Bohlin C. W. , Reardon D. A. , Desjardins A. , Quinn J. A. , Rich J. N. , Bota D. A. , Goli K. , Friedman H. S. , Vredenburgh J. J.
Published: March 2020

12506

Background: Thromboembolic disease is the second leading cause of death in brain tumor patients. Various studies have documented a 20–40% risk of deep vein thrombosis and / or pulmonary embolus in brain tumor patients. When used as prophylaxis, Tinzaparin, a low molecular weight heparin with factor Xa activity, has a low complication rate and low incidence of bleeding complications. With the anticipated benefit exceeding any risk, prophylaxis with Tinzaparin may be safe and effective. Methods: A phase II trial of prophylactic tinzaparin for newly diagnosed brain tumor patients has completed accrual at 40 patients. A fixed daily dose of 4500 IU subcutaneous tinzaparin was given beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients consented to take tinzaparin daily for 12 months. Weekly blood counts were monitored during chemotherapy cycles. Tinzaparin was held if platelet count was <50,000 and resumed once the platelets were >100,000. Tinzaparin was discontinued in patients who began treatment with avastin. Results: Of 40 patients, 7 remain on treatment. Patients have taken tinzaparin for 4–52 weeks with a median of 21 weeks. One of the patients developed a grade 3 CNS hemorrhage and one had a grade 1 CNS hemorrhage, necessitating cessation of the tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. No patients developed = grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking tinzaparin, and three patients developed thromboembolic complications while off tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to tinzaparin. Conclusions: Thus far, daily prophylactic tinzaparin has proven safe and effective in decreasing the incidence of thromboembolic disease in brain tumor patients. We plan a phase III study upon the safe completion of the last 7 patients on this phase II study.

No significant financial relationships to disclose.
A study of feasibility for setting up a dedicated brain tumor registry
Authors: Davidson S. J. , O’Neal K. , van Dellen J. , Roncaroli F. , Brock C. , Waldman A.
Published: March 2020

12514

Background: Population-based tumor registries represent an invaluable resource for monitoring incidence and prevalence of cancer. Nevertheless, data generated is not always useful for deciding treatment protocols or running translational/clinical research. This is particularly true for rare cancers such as primary brain tumors. Moreover, benign or low grade tumors are usually excluded and information such as quality of life and efficacy of treatment not followed up. Finally, there is no agreement on the minimum dataset required. Here, we investigated the difficulties of setting up a dedicated BTR that can be supportive of research. Methods: We audited 1000 consecutive histologically proven adult cases operated between 1995–2005. This group included 734 gliomas, 246 meningiomas and 20 ependymomas. As minimum dataset, we considered demographics, presenting symptoms, site, neuroimaging findings, pathology/WHO grade, extent of surgery, post-operative treatment, relapses and cause of death. To avoid capture/recapture errors we cross-referenced four independent databases (histopathology, imaging, Cancer Specialist and hospital patient database). Results: Overall availability of data was 80% in 1995–2000 and 95% in 2000–2005 when electronic notes were introduced. Missing data were as follow: demographics: 0%; symptoms: 20%; site and neuroimaging 15%; incorrect diagnosis or grade update; 20%; extent of surgery: 5%; post-operative treatment: 15%; follow-up: 10%: cause of death: 15%. Data could not be interpreted in 20% of cases due to transcription errors and use of abbreviations. Conclusion: To fulfil requirements for clinical/translational research (GNOSIS), BTR needs i) dedicated national registries; ii) specialist and professional data collection; iii) registration at the time of pathological diagnosis.

No significant financial relationships to disclose.
Phase I of high dose (HD) temozolomide (TMZ) with peripheral blood stem cell support (PBSCS) rescue in recurrent high grade glioma (HGG)
Authors: Frappaz D. , Pierga J. , Bay J. , Fabbro M. , Djafari L. , Sunyach M.
Published: March 2020

12518

Background: Despite improvements obtained with frontline treatments prognosis of recurrent HGG still remains dismal. HD chemotherapy (CT) suggested a dose-effect relationship in lymphoma and germ cell tumors. HD of TMZ could be a promising way to overcome resistance of HGG to standard schedule of CT Methods: This phase I had as principal objective to determine the Maximal Tolerated Dose (MTD) of HD of TMZ with PBSCS rescue in patients with recurrent HGG under 60 year. The MTD was defined as dose level which 50% of patients (pts) treated experienced a DLT (Dose Limiting Toxicity).The dose escalation was planned for eight dose levels from 300 to 650mg/m2/day over 5 days with CSP reinfusion at D7 according to the Modified Continual Reassessment Method (MCRM). Treatment was administered for one cycle. Results: Eighteen eligible pts were treated with HD of TMZ, all had received prior radiotherapy, 11 pts previous CT. Overall HD TMZ was well tolerated for the 7 evaluated dose levels. The MTD was not yet reached. Not dose limiting toxicities were reported in 12 pts: grade 2: fatigue (6pts), cephalalgia (3pts), nausea (3pts) , skin eruption (2pts), mucositis, FUO, vomiting, diarrhea, zoster, dental abcess, lung infection, septicemia, hepatic. grade 3 bilirubinemia, grade 4 neutropenia (13pts) and thrombocytopenia (4pts). Dose Limiting Toxicities were reported in 2 pts, gr3 cytolysis at level 3 (400mg/m2/day ) 1pt and gr 3 arthritis at level 7 (600mg/m2) 1pt respectively . Main hematological toxicities were gr 4 neutropenia in 13 pts median duration was 8 days, 4 pts had gr4 thrombocytopenia lasting 5 days. All patients were evaluable for tumor response, 2 partial responses were observed at 550 and 600mg/m2 level, 5 pts had a stabilization and a disease progression was reported in 11 patients. Conclusions: This interim analysis demonstrated that HD of TMZ with CSP reinfusion is feasible and well tolerated in patients with recurrent HGG. Nevertheless limited activity reported could be related to a less depletion of O6 alkylguanine transferase with HD than with a protracted schedule. Accrual is still ongoing.

No significant financial relationships to disclose.
High-dose methotrexate and ifosfamide for CNS relapse of aggressive lymphoma
Authors: Fischer L. , Korfel A. , Jahnke K. , Kiewe P. , Thiel E.
Published: March 2020

12524

Background: CNS involvement is a grave complication of malignant lymphoma. Therapy traditionally includes intrathecal chemotherapy, radiotherapy and systemic chemotherapy for concomitant systemic lymphoma. However, optimal therapy has not been established thus far for CNS lymphoma. In this pilot study a combination of systemic high-dose (HD) methotrexate (MTX) and ifosfamide (IFO) was evaluated for toxicity and response rate. Methods: 10 patients (pts.) with CNS relapses of aggressive lymphoma (5 nodal DLBCL, 4 PCNSL/PIOL and 1 T-NHL) were treated. Nine pts. had intracerebral lesions, the meningeal compartment was involved in three. Three pts. had systemic manifestations. Median age was 63 years (32 - 83). Therapy consisted of 4g/m2 MTX (4h infusion on day 1) with dose adjustment for creatinine clearance (CC) < 100ml/min (CC/100 * 4g/m2) and 1.5 to 2g/m2/day IFO (3h infusion day 3 to 5). Supportive therapy included mesna and a leucovorin rescue beginning at 24h after start of MTX. Two pts. were treated with intrathecal chemotherapy before MTX/IFO. Results: A median of 4 cycles chemotherapy was administered. Treatment response was documented in 9 pts. (3 CR, 6 PR), and one patient had stable disease. The toxicity was mainly hematologic with grade 3/4 neutropenia in 6 pts., grade 3/4 thrombocytopenia in 4 pts. and grade 3 anemia in 2 pts. One pat. died from sepsis in neutropenia and one pat. with long-term corticosteroid therapy developed an aspergillus pneumonia grade 3. Nephrotoxicity grade 1/2 was observed in 6 pts.. Four pts. were further treated with HD chemotherapy followed by autologous stem cell transplantation or salvage radio-/chemotherapy. A median progression free survival of 6.5+ months (range 1–41+) for all pts. has been reached with persisting remission after 4 to 41 months in 5 pts.. Conclusions: Systemic combination therapy with MTX and IFO is feasible and exhibits a promising activity in CNS relapses of aggressive lymphoma.

No significant financial relationships to disclose.
Role of Brazilian native medicinal plants on VEGF and PDGF receptors expression by glioblastoma cell line GL-15
Authors: Mathias C. , Nascimento I. , Carvalho G. , Meyer R. , Queiroz A. , Freitas S. , Freire S. , Veloso E. , Barbosa P. , Costa S. , Azevedo C.
Published: March 2020

12532

Background: Malignant gliomas are typically angiogenic and express greater amounts of angiogenic factors. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are prominent glioblastoma-associated multifunctional cytokines that stimulate migration, invasion and angiogenesis. Their receptor inhibiton is considered an important target for anitumoral therapy. Flavonoids obtained from Dimorphandra mollis and Croton betulaster, native medicinal plants from Bahia-Brazil, have been described as proliferation inhibitors of a human glioblastoma derived cell line and reduce VEGF production by GL-15. In this study, VEGF and PDGF receptors expression by GL-15 cultures treated with bevacizumab and flavonoids were evaluated. Methods: GL-15 cultures were treated or not with pendulitin and rutin flavonoids (100μM) and bevacizumab (1μg/mL). After 24 hours VEGF and PDGF receptors were analyzed by flow cytometry using monoclonal antibodies labeled with FITC. Results: Flow cytometry showed that the GL-15 cells expressed PDGFR alfa (10%), PDGFR beta (52%), VEGFR 1 (26%) and VEGFR 2 (95%). It was observed that the pendulitin and rutin flavonoids treated cells showed a reduction on PDGFR alfa expression (2 and 1,6 % respectively) but the other receptors expression was similar to the non-treated or DMSO treated controls. Conclusions: GL-15 human glioblastoma derived cell line expresses receptors to the angiogenic cytokines studied. VEGFR 2 expression was predominant and bevacizumab didn’t alter the receptors production. Flavonoids extracted from D. mollis and C. betulaster seem to have an inhibitory action on the PDGRF alfa expression but not on the others receptors.

No significant financial relationships to disclose.
Comparing carboplatin dose administered to the calculated dose using the Modification of Diet and Renal Disease (MDRD) equation
Authors: Villano J. L. , Bressler L. , Radhakrishnan L. , Cuellar S. , Shord S. S.
Published: March 2020

13003

Background: Renal function assessment is vital for dosing of chemotherapy drugs. GFR is usually estimated by creatinine clearance (CrCl). The MDRD equation is thought to provide a more accurate estimation of GFR than the Cockcroft-Gault or 24-hour CrCl measurement. Although this formula has been validated in kidney disease, it has not been extensively studied in cancer patients. Methods: We retrospectively reviewed records for patients who received carboplatin from the University of Illinois at Chicago for a 4-year study period. General demographic information, carboplatin dose for cycles one to three, and common laboratory parameters at baseline and following cycles one to three were collected. The MDRD derived value of GFR was then used in the Calvert equation to calculate carboplatin dose. This calculated dose was compared to the actual dose administered in the first cycle. From this comparison, the records were divided into two groups: (A) actual vs. calculated dose ≥ 20% and (B) actual vs. calculated dose < 20%. We then assessed toxicity by determining the frequency in each group requiring dose reduction on the second cycle of carboplatin. Results: Data are available for 116 patient comparisons. 78 patient comparisons were in group B with agreement between actual vs. calculated MDRD dose. 38 were in group A with 36 having the actual dose being ≥ 20% less than the MDRD-calculated dose. Wilcoxin and Chi analysis reveals statistical significance for African American, women, lower serum creatinine, and older age for Group A. In Group A, cycle 2 dose reductions were made in 3 cases (8% and due to hematologic). In Group B, cycle 2 dose reductions were made in 12 cases. In 8 of these cases (10%), dose reductions were based on ANC, and in 4 cases dose reductions were made likely on the basis of changes in weight or creatinine. Conclusion: In the comparisons examined to date, differences in carboplatin doses due to different methods of calculation do not appear to significantly influence the frequency of dose reduction. Factors used in calculating MDRD such as age, sex, serum creatinine, and ethnicity were variables associated with ≥ 20% difference in actual vs. calculated MDRD dose.

No significant financial relationships to disclose.
Prevention of base excision repair by TRC102 (methoxyamine) potentiates the anti-tumor activity of pemetrexed in vitro and in vivo
Authors: Liu L. , Bulgar A. , Donze J. , Adams B. J. , Theuer C. P. , Gerson S. L.
Published: March 2020

13005

Background: TRC102 (methoxyamine) reverses resistance to alkylating agents by inhibiting base excision repair (BER; a mechanism of DNA repair), thereby increasing DNA strand breaks and potentiating the anti-tumor activity of alkylating agents without additional toxicity, Based on these data, TRC102 is currently being studied in combination with temozolomide in a phase 1 trial. We hypothesized that inhibition of BER by TRC102 would also increase DNA strand breaks and improve the anti-tumor activity of anti-metabolite chemotherapeutics, including pemetrexed, because these agents also produce AP sites that are recognized and repaired by BER. Methods: Pemetrexed- induced AP sites and BER inhibition was quantified using an apurinic/apyrimidinic (AP) site assay in vitro. Single and double DNA strand breaks were quantified by the Comet assay in vitro and anti-tumor activity was assessed in an in vivo xenograft study of subcutaneously implanted H460 human lung cancer cells. Results: Pemetrexed induced and TRC102 reduced the number of available AP sites in pemetrexed- treated H460 cells (by 60–80%), indicating successful inhibition of BER. TRC102 treatment increased DNA strand breaks in pemetrexed-treated H460 cells (2 fold increase versus treatment with pemetrexed alone). Premetrexed treatment alone and in combination with TRC 102 delayed tumor growth in vivo (tumor growth delay of 4.7 days in the 150 mg/m2 pemetrexed alone group, 5.7 days in the 150 mg/m2 pemetrexed + 2 mg/m2 TRC102 group and 6.9 days in the 150 mg/m2 pemetrexed + 4 mg/m2 TRC102 group); in vivo systemic toxicity was not increased. TRC102 alone had no effect in vitro or in vivo. Conclusions: TRC102 effectively inhibits BER in lung cancer cells treated with pemetrexed. Inhibition of DNA repair by TRC102 results in an increase in DNA strand breaks and improved anti-tumor activity versus treatment with pemetrexed alone. Given its preclinical efficacy and safety profile, study of TRC102 combined with pemetrexed in a phase 1 trial is warranted.

No significant financial relationships to disclose.
The effect of five different administration intervals on the pharmacokinetics (pk) of paclitaxel (PTX) and pegylated liposomal doxorubicin (PLD) association regimen
Authors: Airoldi M. , Cattel L. , Passera R. , Milla P. , Cerutti E. , Pedani F. , Zanon C. , Crova A.
Published: March 2020

13012

Background: The PTX-PLD association is a promising schedule for recurrent head/neck cancer. Their pk behavior could be dependent not only on PTX excipient (polyethoxylated castor oil) interference, but even on different i.v. administration intervals between the two drugs. This study evaluated any possible administration interval-dependent pk interaction, when PLD infusion started 0, 1, 3, 12 or 24 h after PTX infusion end. Methods: 25 patients, affected by recurrent cisplatin pre-treated squamous cell head/neck cancer, were randomized to receive PTX 80 mg/m2 q1w and PLD 12.5 mg/m2 q2w at administration intervals of 0, 1, 3, 12 or 24 h. Pk parameters were evaluated during the first course by non-compartmental analysis, while statistical analysis was performed by non-parametric Kruskal Wallis test. Results: Median PK parameters are reported in the table . PTX pk profile is strongly affected by PLD administration. PTX total exposure is highly reduced, with a consequent increase in Cltot; this alteration is totally due to Kel modifications. On the other side, no statistically significant interactions affected PLD pk parameters. Some in vitro experiments indicate that PLD is able to partially absorb PTX, driving to PTX plasmatic concentration reduction, when PLD is administered at 0–1 h intervals. Conclusions: PLD liposomal components seem to be able to entrap PTX, therefore reducing PTX plasmatic concentrations; so, it is very important to choose the ideal administration interval. In order to avoid pk interaction, the i.v. administration interval between PTX and PLD had to be 3 h at least. For shorter intervals, patients could be underexposed to PTX, with lesser clinical efficacy.

[Table: see text]

No significant financial relationships to disclose.
A mechanistic model predicting hematopoiesis and tumor growth to optimize docetaxel + epirubicin (ET) administration in metastatic breast cancer (MBC): Phase I trial
Authors: You B. , Meille C. , Barbolosi D. , Tranchand B. , Guitton J. , Rioufol C. , Iliadis A. , Freyer G.
Published: March 2020

13013

Background: Mathematical modeling is a powerful approach to provide functional description of a real process. In medicine and biology, models are established on the basis of available clinical observations and biological covariates. Modeling applied in cancer treatment is a valuable tool to perform drug dosage adjustments. We used this methodology to regulate ET administration by predicting haematopoiesis and tumor growth in patients with MBC in a phase I trial. Methods: We developed a mechanistic model to describe leukopoiesis / thrombopoiesis / tumor growth in MBC patients under bimonthly ET + G-CSF. The model was first validated using data from clinical trials [Viens, Am J Clin Oncol. 2001;24:328, Chugai lenograstim database] and prospectively applied to individualize ET administration (dose rate and duration). The model optimizes the drug doses that could minimize the tumour burden while respecting a priori fixed constraints on deepness / duration of neutropenia and thrombocytopenia. First course administration was fixed ahead. At following courses, schedules were individually adjusted. At first dose level, patients received ET: 85/85 mg over a 48 h period with various, electronically- controlled infusion rates every 2 weeks. At dose level 2, doses were 100/100 mg. Results: Between 06/2005 and 06/2006, 3.5 median courses (range: 2–6) were administered to 6 patients (level 1: 3; level 2: 3). Rates of grade 3–4 neutropenia and thrombocytopenia were 47 and 0 % respectively. Observed toxicities were close to those predicted by the model. Predicted vs. observed neutrophil counts linear regression was significant (p<0.001). Moreover, 83 and 95 % weighted residuals were comprised between [-2; +2] at all courses and first course respectively. No grade 3–4 non-hematological toxicity was observed. Partial responses were noted in 2 patients (33%) and disease stabilization in 3 patients (50%). Conclusions: We report the preliminary results of the first trial using mechanistic modeling to improve cancer chemotherapy. Using this approach, we have successfully predicted the behavior of a complex biological system and individualized drugs administration in a phase I trial.

No significant financial relationships to disclose.
Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors
Authors: Chatta G. S. , Rader M. E. , Belani C. P. , Ramalingam S. , Chen E. X. , Cooper M. R. , von Moltke L. L. , Musguire L. A. , Egorin M. J. , Karol M. D.
Published: March 2020

13016

Background: Bortezomib (btz; VELCADE) is a first-in-class small molecule proteasome inhibitor used to treat patients with multiple myeloma and mantle cell lymphoma. In vitro and in vivo studies indicate that btz is primarily metabolized by CYP3A4 and CYP2C19. We conducted a study to evaluate the effect of inhibition of CYP3A4 with ketoconazole (keto) on the PK of btz in humans. Methods: The study enrolled patients with advanced malignancies for whom standard therapy was not available. Patients received btz 1.0mg/m2 (IV) on days 1, 4, 8, and 11 of a 21-day cycle, and were randomized to receive keto 400mg (PO) on days 6, 7, 8, and 9 of either the first or second cycle of treatment. Blood samples for plasma btz determination were collected over 72 hours following the Day 8 dose in Cycles 1 and 2. PK parameters were computed non-compartmentally. PD parameters were derived from an Emax model of percentage proteasome inhibition in whole blood. Results: Of the 21 patients enrolled, 13 had sufficient PK sampling in Cycles 1 and 2 to assess the effect of keto on the PK of btz. No statistically significant difference in AUC0–72h for btz ± keto was observed (p=0.2248). The mean AUC0–72h ratio was 1.22 (90% CI, 0.92–1.61). The exposure-PD relationships for btz ± keto were similar (Table). Adverse events were similar in the presence and absence of keto. Conclusions: Although the AUC0–72h difference was not statistically significant, the 90% CI for the AUC0–72h ratio extends beyond the FDA- specified range of 0.80–1.25 for DDI studies, precluding a declaration of no effect. The presence of a strong CYP3A4 inhibitor increased mean btz exposure by only 22% and had no apparent effect on the exposure-PD relationship.

[Table: see text]

No significant financial relationships to disclose.
Multicenter phase II study of chemo-immunotherapy in the treatment of metastatic breast cancer (MBC)
Authors: Recchia F. , Saggio G. , Di Blasio A. , Amiconi G. , Candeloro G. , Necozione S. , Rea S.
Published: March 2020

13501

Background: Several maintenance chemotherapy (CT) strategies have failed to improve the outcome of MBC. With the aim of enhancing the immune function that could eradicate minimal residual disease, we have previously shown that low dose inteterleukin-2 (IL-2) and 13-cis- retinoic acid (RA) restored the immune function of advanced cancer patients that had a clinical benefit (CB) from CT (Clin Cancer Res, 2001). In this study we report on 100 consecutive patients with MBC treated with sequential CT and immunotherapy. Methods: Patients with MBC were eligible if they had no evidence of progression after 6–8 courses of an anthracycline-paclitaxel induction CT. Treatment consisted of IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1- week rest, with intermittent schedules, until progression. Hormonal therapy was given to estrogen receptor (ER) + patients. In order to increase ER expression, beta interferon (1 X 106 IU) was added, subcutaneously, twice a week, to 10 patients with low ER content. Primary endpoint was progression-free survival (PFS); secondary endpoints were toxicity, overall survival (OS) and the evaluation of immunological parameters. Results: From 9/1996 to 9/2001, 100 consecutive patients (median age of 59 years), exhibiting a CB from CT were entered into the study. Grade 2 cutaneous toxicity and fever occurred in 19% and 16% of patients, respectively, while grade 2 autoimmune reaction was observed in 10% of patients. After a median follow-up of 49 months, overall median PFS and OS were 37.1 months and 57.5 months, respectively. Patients with ER+ tumors had a similar response rate to that of patients with ER- tumors but had significantly longer PFS (medians of 44.7 and 32.7 months, respectively) and OS (medians of 64.5 and 51.4 months, respectively). With respect to baseline values, a statistically significant decrease of vascular endothelial growth factor (VEGF) and an improvement in lymphocyte, natural killer cell count and CD4+/CD8+ ratio were observed. Conclusions: IL-2 and RA treatment of women with MBC who achieve a CB after 6–8 courses of anthracycline-paclitaxel based CT, is well tolerated, decreases VEGF, improves the immunological parameters, and seems to delay disease recurrence. A randomized trial is warranted.

No significant financial relationships to disclose.
Synergistic antitumor efficacy and altered gene expression signature in breast cancer cells treated with immunotoxins and cyclosporin A
Authors: Fodstad O. , Xi Y. , Risberg K. , Ju J. , Anderson Y. G.
Published: March 2020

13505

Background: Immunotoxins (ITs) has shown limited clinical success related to liver toxicity and development of anti-IT antibodies. To delay the immune response we tested combinations of ITs and the Cyclosporin A (CsA). we have shown that one IT, currently in a phase I/II clinical trial, acts by inducing apoptosis and protein synthesis inhibition, but gene expression analysis of IT treated cells has never been reported. Hence, we also studied changes in gene expression induced by ITs alone and the effects of adding (CsA) on both treatment efficacy and gene expression signature. Methods: Human MA-11 breast cancer cells were treated in vitro with antiEGFR- and antiEPCAM-based ITs alone and in combinations with CsA. Therapeutic efficay was assessed by MTS cell viability assay. Total RNA from untreated and treated cells was isolated and CodeLink Uniset Human 20 k Oligo Bioarray (GE Healthcare, Amersham Biosciences, NJ), containing approximately 20,289 gene probes, was used to generate gene expression profiles. Gene expression analysis was carried out using GeneSpring software version 7.2 using One-way ANOVA with p<0.05. Comparisons of gene list across different groups were performed using Venn Diagrams. Results: Combination therapy produced remarkable synergistic effects in MA-11 cells in vitro and in metastasis models in vivo. Moreover, in conventional rats receiving repeated injections of ITs and CsA the formation of anti-IT antibodies was virtually abrogated. Changes in gene expression profiles induced by the ITs alone and in combination with CsA were evaluated to elucidate the underlying molecular mechanisms for the synergistic effects. The ITs each induced specific changes in expression of some apoptosis-related genes but also fogenes in pathways unrelated to apoptosis and protein synthesis. The addition of CsA induced up- or down-regulation of a number of interesting non-immune-associated genes Conclusions: Important shortcomings for successful clinical use of ITs may be overcome by combination therapy with CsA. The possibility for further improvement is provided by results of gene profiling studies identifying therapy-induced genes belonging to different cell signaling pathways.

No significant financial relationships to disclose.
Preclinical activity of combinations of capecitabine (C), docetaxel (D), and trastuzumab (T) in a breast cancer xenograft model
Authors: Kolinsky K. , Zhang Y. , Moisa C. , Dugan U. , Packman K. , Higgins B.
Published: March 2020

13508

Background: C is highly active, well tolerated, and extends survival when added to D in pretreated metastatic BC. We report preclinical data on CD doublets ± T, a humanized monoclonal antibody against HER2-neu, in the KPL-4 human BC xenograft model (ER-, HER2+). Methods: Initially, the antitumor activity of optimal dose (OD) and ½ OD C and D monotherapy was evaluated alongside ½ OD C + ½ OD D or ½ OD C + OD D. Data showed ½ OD C + OD D was toxic; thus, OD C + OD D was not considered further. The OD C + ½ OD D doublet and the optimal doublet from the initial study (½ OD C + ½ OD D) were tested ± T in this HER2+ model. Results: In the initial study, tumor response (TR) and increased life span (ILS) were significantly better for ½ OD C + ½ OD D than for ½ OD C, OD C, ½ OD D, or OD D. In the follow-up study, TR and ILS were not significantly different in the ½ OD C + ½ OD D and OD C + ½ OD D doublets but were better with the addition of T to each doublet. In comparing triplicates, TR was not statistically different, and survival was equivalent at this point because of complete responses (CRs) in both groups. At day 127, there were 2/10 CRs in the ½ OD C + ½ OD D + T group (ILS=267%) vs 6/10 CRs in the OD C + ½ OD D + T group (ILS>370%, ongoing). Conclusions: Adding T to the non-toxic CD doublets increases TR and ILS. Thus far, results argue for the most dense dose of C in triplicate combinations for sustaining CRs. However, since CRs are present in both triplicate groups of limited sample size (n=10), an overall survival difference is not yet significant. The data support clinical testing of CD doublets with or without T, which is ongoing in the neoadjuvant setting in HER2- and HER2+ BC patients, respectively.

[Table: see text]

No significant financial relationships to disclose.
A trial of vaccination with the carcinoembryonic antigen (CEA) peptide CAP 1–6D with montanide ISA 51 adjuvant or granulocyte- macrophage colony stimulating factor (GM-CSF) in HLA-A2+ patients with CEA producing adenocarcinomas of gastrointestinal (GI) track
Authors: Whitehead R. P. , Jantz K. , Simmons A.
Published: March 2020

13513

Advances in drug therapy have improved the survival of patients with GI tumors but most patients with metastatic disease are not cured. Immunotherapy is an additional modality of treatment. In this trial, the CEA peptide, CAP 1–6D, was combined with either GM-CSF or montanide ISA 51 as adjuvants and used to vaccinate patients with CEA producing GI tumors. End points were development of peptide responsive immunity, toxicity, and anti-tumor effects. To be eligible, patients were required to have a histologic diagnosis of adenocaricnoma of GI tract origin with a life expectancy of at least 6 months and to have either metastatic disease or to have completed standard adjuvant therapy after resection. Patients were required to have a CEA producing tumor, be HLA-A2 positive, have a performance status of 0–1, test negative for HIV, hepatitis B and C, and have adequate bone marrow, liver and kidney function. Treatment consisted of 1 mg of CAP 1–6D peptide combined with either 250 ug of GM-CSF given intradermally, or 2 ml of Montanide ISA 51 given subcutaneously every 3 weeks for 6 treatments. Blood was drawn for ELISpot assay at each visit. Nine (out of a planned 10) patients, 8 with colorectal cancer and 1 with pancreatic cancer, were entered before the peptide was deemed expired and withdrawn from clinical use by the NCI. Of five colorectal patients with metastatic disease at baseline 4 progressed and 1 had stable disease. The pancreatic cancer patient was treated adjuvantly but progressed during therapy. Three colorectal cancer patients treated adjuvantly were free of disease at baseline and at the completion of therapy. Treatments were well tolerated. ELISpot data on 5 patients showed that 4 patients developed peptide responsive immunity. Responsive patients included those receiving either GM-CSF or Montanide ISA 51 and both adjuvantly treated and progressive metastatic colorectal patients and the progressed pancreatic cancer patient. This vaccine regimen can be safely given to cancer patients and can produce peptide responsive immunity in the ELISpot assay but this does not correlate with clinical anti-tumor effect.

No significant financial relationships to disclose.
Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors
Authors: Price T. J. , Lipton L. , Williams J. , McGreivy J. , McCoy S. , Sun Y. , Aguero-O’Neill B. , Rosenthal M. A.
Published: March 2020

14005

Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented.

[Table: see text]

No significant financial relationships to disclose.