Prior Platinum Treatment Research Articles

A real-world study of treatment patterns following disease progression in epithelial ovarian cancer patients undergoing poly-ADP-ribose polymerase inhibitor maintenance therapy

BackgroundThe efficacy of subsequent therapy after poly-ADP-ribose polymerase (PARP) inhibitor maintenance treatment has raised concerns. Retrospective studies show worse outcomes for platinum-based chemotherapy after progression of PARP inhibitor-maintenance therapy, especially in BRCA-mutant patients. We aimed to describe subsequent therapy in ovarian cancer patients after PARP inhibitor-maintenance therapy and evaluate their response to treatment. We focused on chemotherapy for patients with a progression-free interval (PFI) of ≥ 6 months after prior platinum treatment, based on BRCA status.MethodsWe analyzed real-world data from Peking University Cancer Hospital, subsequent therapy after progression to PARP inhibitor-maintenance therapy for epithelial ovarian cancer between January 2016 and December 2022. Clinicopathological characteristics and treatment outcomes were extracted from medical records. The last follow-up was in May 2023.ResultsA total of 102 patients were included, of which 29 (28.4%) had a germline BRCA1/2 mutation and 73 (71.6%) exhibited BRCA1/2 wild-type mutations. The PARP inhibitors used were Olaparib (n = 62, 60.8%), Niraparib (n = 35, 34.3%), and others (n = 5, 4.9%). The overall response rate (ORR) was 41.2%, and the median time to second progression (mTTSP) was 8.1 months (95%CI 5.8–10.2). Of 91 platinum-sensitive patients (PFI ≥ 6 months) after progression to PARP inhibitor-maintenance therapy, 65 patients subsequently received platinum regimens. Among them, 30 had received one line of chemotherapy before PARP inhibitor-maintenance therapy. Analysis of these 30 patients by BRCA status showed an ORR of 16.7% versus 33.3% and mTTSP of 7.1 (95% CI 4.9–9.1) versus 6.2 months (95% CI 3.7–8.3, P = 0.550), for BRCA-mutant and wild-type patients, respectively. For the remaining 35 patients who had received two or more lines of chemotherapy before PARP inhibitor-maintenance therapy, ORR was 57.1% versus 42.9%, and mTTSP was 18.0 (95% CI 5.0–31.0) versus 8.0 months (95% CI 4.9–11.1, P = 0.199), for BRCA-mutant and wild-type patients, respectively.ConclusionNo differences in survival outcomes were observed among patients with different BRCA statuses. Furthermore, for patients who had undergone two or more lines of chemotherapy before PARP inhibitor maintenance therapy, no negative effects of PARP inhibitors on subsequent treatment were found, regardless of BRCA status.

Abstract B035: Cyclin E1 positive staining is frequent and independent of prior platinum treatment in high grade serous ovarian cancer

Abstract B035: Cyclin E1 positive staining is frequent and independent of prior platinum treatment in high grade serous ovarian cancer

Erstlinientherapie des metastasierten Urothelkarzinoms: ein Update

BackgroundUrothelial carcinoma (UC) of the bladder is considered to be a tumor sensitive to chemotherapy. Nevertheless, the 5‑year survival rate in stage IV is < 5%. Approximately half of the patients receive only first-line treatment due to rapid disease progression and/or poor general condition.ObjectiveNarrative review of the first-line treatment of advanced UC.Material and methodsEvaluation of treatment recommendations of national and international guidelines as well as a literature search in PubMed and congress abstracts.ResultsCrucial for the choice of first-line treatment is the (cis)platinum eligibility. If possible, a chemotherapy combination containing cisplatin should be carried out. In cases of contraindications, cisplatin can be replaced by carboplatin but at the cost of a loss of efficacy. If at least stable disease is achieved after 4–6 cycles of treatment containing platinum, immune maintenance therapy with avelumab should be subsequently applied. The programmed cell death 1 ligand 1 (PD-L1) inhibitor showed a survival benefit compared with best supportive care (BSC) regardless of prior platinum treatment or cycle number. Patients with (cis)platinum ineligibility and positive PD-L1 status can receive immuno-monotherapy with atezolizumab or pembrolizumab. For the remaining patients, an individual decision has to be made whether and which systemic treatment should be considered or whether a BSC approach should be favored.ConclusionThe course of the disease is set early, before initiation of first-line treatment, with the determination of (cis)platinum eligibility. Avelumab is the first immune maintenance treatment available with significant survival benefit.

Real-World Patient Characteristics and Time on Treatment Outcomes Among Patients Receiving First-Line Pembrolizumab in the Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC) in the United States

<h3>Purpose/Objective(s)</h3> In July 2019, the FDA approved pembrolizumab in combination with platinum and fluorouracil (P+C), or as monotherapy [P, in combined positive score (CPS) ≥1 population], for the first-line (1L) treatment of patients with R/M HNSCC based on KEYNOTE-048 trial results. Limited evidence exists on the real-world use of pembrolizumab therapy post-approval. The objective of this study was to assess demographic and clinical characteristics, and treatment patterns among patients initiating pembrolizumab therapy in 1L R/M HNSCC. <h3>Materials/Methods</h3> A retrospective cohort study was conducted using the Flatiron Health Advanced Head and Neck database. The study cohort included adult R/M HNSCC patients, who initiated 1L P or P+C between 07/01/2019 - 12/31/2020. Patients were excluded if they received prior platinum treatment ≤6 months of 1L pembrolizumab therapy, had other primary cancers before R/M HNSCC diagnosis, or were treated with a clinical study drug. Real-world time on treatment (rwToT) was assessed using Kaplan-Meier methods. <h3>Results</h3> A total of 402 patients initiated 1L pembrolizumab therapy, [P (n=264), P+C (n=138)]. Descriptive analyses showed differences between patients receiving P versus P+C (Table 1). Patients receiving P were older, and more likely to have a history of smoking, being HPV positive, and have higher ECOG score at 1L initiation. Other patient characteristics were similar between P versus P+C. Treatment pattern results showed that 68.2% (P: 72.0%, P+C: 60.9%) of pembrolizumab treated patients had a record of PD-L1 test before or within 30 days of 1L initiation in the data. Majority of these PD-L1 tests assessed CPS scores (71.8%) with 82.2% of patients CPS≥1 (P 85.8%, P+C 73.2%). The median 1L rwToT was 3.9 months (IQR: 1.4-8.5) for P and 4.9 months (IQR: 1.6−10.4) for P+C, consistent with the results of the KEYNOTE-048 trial [P: 3.5 months (IQR: 1.4-7.6), P+C: 5.8 months (IQR: 2.8-9.7)]. <h3>Conclusion</h3> In our real-world study, some patient differences regarding patient characteristics were observed between patients initiating P vs. P+C. Furthermore, 1L use of pembrolizumab was observed in a severe R/M HNSCC population (ECOG ≥ 2). rwTOT with P and P+C were consistent with results of the KEYNOTE-048 trial, thus validating trial results. Table 1. Baseline characteristics of patients initiating 1L P versus P+C

Abstract CT234: VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort

Abstract [BACKGROUND]Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or germline or somatic homologous recombinant repair mutation (g/sHRRmt), and advanced serous ovarian cancer that are homologous recombination deficiency (HRD)-positive, g/sBRCAmt or sensitive to prior platinum treatment. However, there is limited knowledge about the efficacy of PARP inhibitors in other cancers with HRD with or without gBRCAmt, in platinum-resistant settings, and about efficacy after prior PARP inhibitor treatment. IDX-1197 is a new PARP inhibitor which is active against cell lines with acquired resistance to platinum and PARP inhibitors. VASTUS study is a basket trial composed of 9 different cohorts investigating use of IDX-1197 in various tumors known to be responsive to PARP inhibitors, as well as in tumors and settings that have not been well-investigated so far. [METHOD]VASTUS is a multi-center, basket trial (NCT04174716) to evaluate safety and efficacy of IDX-1197 as a monotherapy in 1) cancers that are known to be responsive to PARP inhibitors (breast cancer, ovarian cancer, and pancreatic cancer), 2) cancers where PARP inhibitors' safety and efficacy have not been confirmed (small cell lung cancer, biliary tract cancer, uroepithelial cancer, and gastric cancer), 3) any solid tumors resistant to prior platinum-based therapy, excluding refractory to prior platinum based therapy, and 4) any solid tumors that have been exposed to prior PARP inhibitors. In VASTUS trial, patients are selected by pathogenic mutations in HRD-related genes. In the cohort for tumors with prior exposure to PARP inhibitors, patients are eligible regardless of gene mutations as long as they have received prior PARP inhibitor. Study is composed of two parts – phase 1b to assess safety and tolerability of IDX-1197 and to determine recommended phase 2 dose; after review by data safety monitoring committee and go/no-go decision, phase 2a will be commenced to assess the efficacy of IDX-1197 based on objective response rate (ORR). Retrospective translational researches with tumor tissue and peripheral blood are planned (circulating tumor DNA), specifically for prior PARP inhibitor exposure cohort. As of 05 Jan 2021, 32 patients have been enrolled. Citation Format: Kyung-Hun Lee, Ahrum Min, Hee Kyung Ahn, Keun Seok Lee, Yong Wha Moon, Seung Tae Kim, Jeong Eun Kim, Joo Hyuk Sohn, Il Hwan Kim, Woo Kyun Bae, Myong Jae Lee, Eun-Jihn Roh, Chan-Young Ock, Won Sik Lee, Seock-Ah Im. VASTUS - a phase 1b/2a basket trial of a new PARP inhibitor, IDX-1197, including PARP inhibitor resistant cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT234.

Evaluation of efficacy and safety of PARP inhibitors in breast cancer: A systematic review and meta-analysis

BackgroundMany breast cancer clinical trials with PARPi have been completed or are currently carried out, either by monotherapy or combined with chemotherapy. We aim to assess the efficacy and safety of PARPi in breast cancer patients as compared to chemotherapy. MethodsA comprehensive literature search of PubMed, EMBASE, CENTRAL, conference meetings and clinical trial registry was performed. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR). The secondary outcome was safety profile. The comparative effects were measured using hazard ratio (HR) or relative risk (RR) with 95% confidence interval. Subgroup analyses were conducted based on types of intervention and baseline characteristics of patients. ResultsSix RCTs (n = 1953) were included. Two RCTs were recognized as high risk. PARPi was associated with an improved PFS (HR, 0.65; 95% CI, 0.56–0.74), OS (HR, 0.86; 95% CI, 0.73–1.01), and a higher ORR (RR, 1.38; 95% CI, 1.05–1.82). PARPi, however, significantly increased risk of grade 3–4 thrombocytopenia (RR, 1.63; 95% CI, 1.06–2.52). Monotherapy was observed with lower risk of disease progression and higher ORR rate than combination therapy, 0.56 to 0.65 and 2.21 to 1.05, respectively. For patients without prior platinum treatment, PARPi significantly improved PFS (HR, 0.64; 95% CI, 0.52–0.79). ConclusionsPARPi was observed with a significantly improved efficacy in aspects of PFS and ORR, but also higher risk of grade 3–4 thrombocytopenia as compared to chemotherapy. PARPi was a better choice for patients who had not received previous platinum treatment.

Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC).

9515 Background: Pralsetinib is an investigational, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations. We provide the registrational dataset for pts with RET fusion+ NSCLC with and without prior treatment from the global ARROW study. Methods: ARROW (75 sites in 11 countries; NCT03037385) consists of a phase I dose escalation to establish recommended phase II dose (400 mg once daily [QD] orally) and phase II expansion cohorts defined by tumor type and/or RET alteration. Primary objectives were overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Efficacy analyses are shown for response-evaluable pts (REP) with RET fusion+ NSCLC who initiated 400 mg QD pralsetinib by July 11 2019 and safety for all pts (regardless of diagnosis) treated with 400 mg QD. Results: As of November 18 2019, 354 pts with advanced solid tumors had received pralsetinib at starting dose of 400 mg QD with median follow-up 8.8 months. ORR, disease control rate (DCR), and % of pts with tumor size reduction are shown in the table for pts with metastatic RET fusion+ NSCLC (n=116; 72% KIF5B; 16% CCDC6; 12% other/fusion present but type unknown) and with prior platinum treatment (n=80) or without prior systemic treatment (n=26). ORR was similar regardless of RET fusion partner, prior therapies, or central nervous system involvement. Overall there were 7 (6%) complete responses, 4 (5%) in prior platinum pts and 3 (12%) in treatment naïve pts; median time to response overall was 1.8 months and median duration of response (DOR) was not reached (95% CI, 11.3–NR). In the safety population (n=354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). 4% of pts in the safety population (all tumor types) discontinued due to TRAEs. Conclusions: Updated, registrational, centrally reviewed data demonstrate that pralsetinib has rapid, potent, and durable clinical activity in pts with advanced RET fusion+ NSCLC regardless of RET fusion genotype or prior therapies, and QD oral dosing is well-tolerated. Clinical trial information: NCT03037385 . [Table: see text]

303P - EMBRACA: Comparison of efficacy and safety of talazoparib (TALA) and physician's choice of therapy (PCT) in patients (pts) with advanced breast cancer (aBC), a germline BRCA1/2 mutation (gBRCAm), and prior platinum treatment

303P - EMBRACA: Comparison of efficacy and safety of talazoparib (TALA) and physician's choice of therapy (PCT) in patients (pts) with advanced breast cancer (aBC), a germline BRCA1/2 mutation (gBRCAm), and prior platinum treatment

Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma.

286 Background: Anti-PD-L1 immunotherapy has shown promising clinical activity in urothelial carcinoma (UC). We report on a planned update of efficacy and follow-up in patients (pts) receiving durvalumab for the treatment of locally advanced or metastatic UC. Methods: Pts received durvalumab 10 mg/kg Q2W up to 12 months (mo), unacceptable toxicity or confirmed progressive disease. Tumor PD-L1 expression was assessed using the validated Ventana SP263 assay (PD-L1 high = TC ≥ 25% or IC ≥ 25%). Primary endpoints were confirmed ORR by RECIST v1.1 with blinded independent central review (BICR) and safety. Duration of response (DoR) and overall survival (OS) were key secondary endpoints. Results: As of July 24, 2016 (data cutoff [DCO]), the primary efficacy population included 103 pts who were followed for at least 13 weeks (median duration of follow up 7.3 mo); 37% had ≥ 2 prior regimens; 97% had prior platinum treatment; 95% had visceral metastases; and 49% had liver metastases at baseline. As of the DCO, 21 pts (20.4%) had a confirmed response per BICR (including 5 pts [4.9%] with a complete response) and an additional 3 pts had an unconfirmed response. Responses were seen in both PD-L1 high and PD-L1 low/negative subgroups (Table). Responses occurred early (median time to response 1.4 mo) and were durable. Median DoR has not been reached. Of the 21 confirmed responders, 18 pts had an ongoing response, 16 pts had DoR ≥ 6 mo and 7 pts had DoR ≥ 9 mo. Treatment-related Grade 3/4 AE rates were low (5.2%; as treated population, n = 191); Grade 3/4 immune-mediated AEs (imAEs) occurred in 3 pts, and 1 pt discontinued treatment due to an imAE of acute kidney injury. Conclusions: Durvalumab administered at 10 mg/kg Q2W showed clinical activity and an excellent safety profile in pts with locally advanced or metastatic UC. Clinical trial information: NCT01693562. [Table: see text]

Abstract OT1-1-12: A phase 3, open-label, randomized, parallel, 2-arm multi-center study of the oral PARP inhibitor BMN 673 versus physician's choice in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA study)

Abstract Background: Poly-ADP-ribose polymerase (PARP) represents a family of enzymes of which at least two (PARP1 and PARP2) play important roles in DNA repair. PARP inhibition induces synthetic lethality in tumor cells bearing mutations in the genes encoding breast cancer susceptibility gene 1 (BRCA 1) and breast cancer susceptibility gene 2 (BRCA 2), both of which are key components in the pathway of homologous recombination DNA repair. BMN 673 is the most potent preclinical PARP inhibitor described to date with the highest efficiency at trapping PARP-DNA complexes (Murai et al, 2014). BMN 673 is a novel and highly potent PARP inhibitor and has shown promising single-agent anti-tumor efficacy in several tumor types in an ongoing Phase 1/2 clinical study. Methods: The purpose of this multi-center, international, open-label, 2:1 randomized Phase 3 trial (EMBRACA) is to compare the safety and efficacy of BMN 673 versus protocol-specific physician’s choice treatment (capecitabine, eribulin, gemcitabine or vinorelbine) in subjects who have locally advanced and/or metastatic breast cancer with germline BRCA mutations. The primary objective of the study is to compare progression free survival (PFS) of subjects treated with BMN 673 as a monotherapy relative to those treated with protocol-specific physician’s choice treatment. Secondary objectives include objective response rate (ORR), overall survival (OS), safety and pharmacokinetics of BMN 673. Exploratory objectives include duration of response (DOR) and health-related quality of life assessment. Patients may be eligible if they are 18 years or older, have histologically or cytologically confirmed carcinoma of the breast, locally advanced and/or metastatic disease appropriate for systemic single cytotoxic chemotherapy, documentation of a deleterious or pathogenic germline BRCA1 or BRCA2 mutation, ≤ 2 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease, prior treatment with a taxane and/or anthracycline in the adjuvant or metastatic setting, ECOG performance status ≤ 1, and no prior platinum treatment for metastatic disease. Patients (n=429) will be randomized 2:1 to receive either BMN 673 oral capsules once daily (1.0 mg/day) in 21-day cycles or protocol-specific physician’s choice treatment. All eligible subjects will receive study drug treatment until disease progression or unacceptable toxicity. This trial is enrolling patients from the United States, Europe, Israel, Asia/Pacific, and South America (NCT01945775). Citation Format: Jennifer K Litton, Joanne L Blum, Wolfgang Eiermann, Young-Hyuck Im, Miguel Martin, Lida Mina, Henri Roché, Hope S Rugo, Frances Visco, Charlie Zhang, Nathalie A Lokker, Debra L Lounsbury. A phase 3, open-label, randomized, parallel, 2-arm multi-center study of the oral PARP inhibitor BMN 673 versus physician's choice in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-12.

P1.01 - A phase 3 study of the oral PARP inhibitor talazoparib (BMN 673) in BRCA mutation subjects with advanced breast cancer (EMBRACA)

ABSTRACT Background: Poly-ADP-ribose polymerase (PARP) enzymes are important in DNA repair. PARP inhibition induces lethality in tumor cells with mutations in the genes encoding breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2). Talazoparib (BMN 673) is a novel, dual-mechanism PARP inhibitor that both potently inhibits the PARP enzyme and effectively traps PARP on DNA, resulting in cell death in BRCA1/2-mutated cells.[ 1 , 2 ] Talazoparib has shown promising single-agent antitumor efficacy in several solid tumor types and generally well tolerated in an ongoing Phase 1/2 clinical study[ 3 ]. Methods: This multi-center, global, Phase 3 trial (EMBRACA) compares the safety and efficacy of talazoparib versus physician's choice treatment (capecitabine, eribulin, gemcitabine or vinorelbine) in locally advanced and/or metastatic breast cancer subjects with germline BRCA mutations. The primary study objective is to evaluate progression-free survival (PFS) in subjects treated with talazoparib as a monotherapy compared with those treated with protocol-specific physician's choice. Secondary objectives include objective response rate (ORR), overall survival (OS), and safety. Patients may be eligible if they are ≥18 years, have histologically/cytologically confirmed breast carcinoma, locally advanced and/or metastatic disease, documentation of a deleterious or pathogenic germline BRCA1 or BRCA2 mutation, ≤2 prior chemotherapy-inclusive regimens for locally advanced and/or metastatic disease, prior treatment with a taxane and/or anthracycline in the adjuvant or metastatic setting, ECOG performance status ≤1, and no prior platinum treatment for metastatic disease. Patients (n = 429) will be randomized 2:1 to receive either talazoparib oral capsules (1.0mg/day, 21-day cycles) or physician's choice treatment. All eligible subjects will receive study drug treatment until disease progression or unacceptable toxicity. This trial is enrolling patients from Europe, Asia/Pacific, Israel, South America, and the United States (NCT01945775).

Abstract 1188: BRCA 1/2 mutation status is correlated with increased hypersensitivity reactions to carboplatin.

Abstract Background: Carboplatin (Cp) has become the standard first-line chemotherapeutic agent for treatment of ovarian cancer (OvCa), and Cp-related hypersensitivity reaction (HSR) has been observed in 5-20% of patients (pts). The several known potential risk factors for HSR include age, # of prior platinum treatments/cycles, and longer duration of platinum-free interval (PFI). The role of BRCA mutation status has not been studied in the context of Cp HSR, although OvCa pts with BRCAmut+ are treated repeatedly with platinum-based chemotherapies. Methods: The medical records of 74 women who enrolled and initiated at least one cycle of Cp on two phase I clinical trials (NCT01237067 and NCT01445418) with Cp and olaparib (AZD2281) were reviewed. Cp was given with olaparib for a maximum of 8 cycles. Clinical characteristics including BRCA mutation status, history of HSR prior to or on study, and outcomes were analyzed. Results: Primary diagnoses of the 74 pts were ovarian (71), fallopian tube (1), and primary peritoneal (2) carcinomas. Pts had a median age of 56 years (27-80) and ECOG 0-1. 50/74 (68%) pts were BRCA mutation carriers (BRCA 1 [38], BRCA 2 [10], BRCA1/2 [1], BRCApro 68% [1]). All pts had received platinum-based therapy prior to enrollment, and the median # of prior platinum regimens and cycles were 2 (1-6) and 12 (2-42), respectively. The median PFI from the last prior platinum treatment to the first Cp infusion on study was 15.3 months (6-82). 15/74 (20%) pts had a documented history of HSR to Cp prior to enrollment and were pre-medicated with methylprednisolone, H1, and H2 blockers before a slow, incremental Cp infusion. 15/74 (20%) pts developed HSR on study (grade 1 [6], grade 2 [5], and grade 3 [4]), 4 of whom had prior history of Cp HSR. Taken together, the incidence of Cp HSR at any point in the pts’ oncologic history, either prior to or on study, was 35.1% (26/74); prior history of Cp HSR was not predictive of HSR on study. Age, median # of prior platinum cycles, and PFI for the 15 pts with HSR on study vs. those with no HSR history were 52 (27-73) vs. 56 (34-73), 12 (6-20) vs. 10 (2-42), and 21.2 (8-53) vs. 15.3 (6-82), respectively, all of which were not statistically significant. 4/15 (27%) pts with HSR on study (including 2/4 pts with prior history) stopped Cp treatment due to repeated HSR despite pre-medications, while 7/15 (47%) pts stopped therapy for other reasons. The remaining 4/15 (27%) pts successfully completed 8 cycles or are continuing therapy per protocol. BRCA mutation was significantly associated with increased risk of HSR (prior to or on study), 46% (23/50), vs. 11% (2/19) for pts with no BRCA mutation (p = 0.010). Conclusions: Cp re-treatment can be successful for OvCa pts despite prior history of HSR. Prior HSR history did not increase the risk of HSR on study. Being a BRCAmut+ carrier was associated with a statistically significantly greater risk of HSR and may serve as a clinical predictive biomarker of Cp hypersensitivity. Citation Format: Dominic H. Moon, John L. Hays, Christina M. Annunziata, Anne M. Noonan, Lori Minasian, Nicole Houston, Elise C. Kohn, Jung-min Lee. BRCA 1/2 mutation status is correlated with increased hypersensitivity reactions to carboplatin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1188. doi:10.1158/1538-7445.AM2013-1188

P3-16-05: A Phase II Trial Expansion Cohort of the PARP Inhibitor Veliparib (ABT888) and Temozolomide in BRCA1/2 Associated Metastatic Breast Cancer.

Abstract Background: Veliparib (ABT-888) is a novel oral inhibitor of Poly (ADP-Ribose) Polymerase (PARP) 1 and 2. Veliparib and temozolomide (TMZ) are synergistic in breast cancer xenograft models. We recently conducted a phase II study of TMZ and veliparib in 41 patients (pts) with metastatic breast cancer (MBC). Activity was observed only in pts with known BRCA1 or BRCA2 deleterious mutations, with a response rate (RR) of 50% (4/8) and clinical benefit rate (CBR) of 62.5%. In order to further evaluate the activity and safety of TMZ and veliparib, we enrolled an expansion cohort of 20 additional patients with BRCA1 or 2 mutations. Methods: We previously conducted a single arm phase II trial of veliparib and TMZ in 41 MBC pts. Eligibility included measurable disease, ≥1 prior MBC therapy and PS ≤ 2. Available archived tumor samples were collected. In this expansion cohort, first line therapy for MBC and prior PARP inihibitor therapy were allowed, and eligible patients were required to have a known deleterious BRCA1 or BRCA2 mutation identified from prior clinical testing. The dose of veliparib in the original cohort was reduced from 40 mg PO BID to 30 mg PO BID. In the expansion cohort all patients received veliparib (30 mg PO BID days 1–7) and TMZ (150mg/m2 PO QD days 1–5) on a 28 day cycle. RECIST response was evaluated every 2 cycles. The primary endpoint was overall response rate. Secondary endpoints included PFS, OS, safety and toxicity. Results: Between June 24, 2010 and Sept 29, 2010, 20 eligible pts (median age 42) were enrolled. Baseline characteristics included: median PS=0 (range 0–2); 9 BRCA1 carriers, 9 BRCA2 carriers, and 2 unknown. 17 pts (85%) received prior adjuvant chemotherapy. 9 patients received a prior platinum chemotherapy. The most common grade 3/4 toxicities included thrombocytopenia and neutropenia. Best response for the 20 patients evaluable at the time of abstract submission includes 3 PR (15%), 6 SD (30%), 11 PD, and a clinical benefit rate of 45%. Combined with the initial cohort of 8 known carriers from the original 41 patients, the total RR is 25% (7/28) and clinical benefit rate of 50% (7 PR, 7 SD). The RR was 40% (6/15) in pts without prior platinum treatment, and 9% (1/11) in pts with prior platinum treatment. The median PFS for the 20 BRCA carriers was 85 days, and among patients with prior platinum treatment compared to no prior platinum, the median PFS was 70 and 179 days, respectively. Three pts remain on study, 1 with a CR for &amp;gt;20 mo. Discussion: We previously demonstrated that veliparib and TMZ is an active combination in BRCA1/2 associated MBC. In this larger expansion cohort of 20 additional patients, the combination continued to show activity, although the response rate was not as robust as previously observed. Differences between the original cohort and the expansion cohort may account for some variation in response, such as prior platinum or PARP inhibitors therapy, number of lines of prior therapy, and the dose of veliparib used (40mg vs 30 mg). These results support further evaluation of this regimen in the BRCA1/2 carrier population, and provide the opportunity to evaluate potential factors that may predict response or resistance to this regimen. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-05.

Epithelial Ovarian Cancer: Role of Pegylated Liposomal Doxorubicin in Prolonging the Platinum-Free Interval and Cancer Antigen 125 Trends During Treatment

Epithelial ovarian cancer's response to platinum retreatment depends on the duration of response to first-line platinum therapy. Platinum-free interval predicts subsequent platinum sensitivity and is a prognostic factor. Little has been published on the effect of pegylated liposomal doxorubicin (PLD) in the prolongation of treatment-free interval. Patients treated with PLD were reviewed to assess response to platinum retreatment after PLD and to establish the use of cancer antigen 125 (Ca125) trends. All patients treated with PLD had progressed within 12 months of prior platinum therapy. Cancer antigen 125 fluctuations were categorized as the variances from the baseline (+/-10%, +/-10%-25%, and >25%). The response to chemotherapy was defined as Ca125 reduction from the baseline of more than 50%, clinical, or radiological response. Fifty-nine women were identified. The response rate (RR) to PLD was 28.9%, and the median overall survival from PLD initiation was 62 weeks. The number of women demonstrating more than 25% reduction in Ca125 from the baseline increased progressively with each cycle; at cycle 2, 11%; cycle 3, 18%; cycle 4, 22%; and cycle 5, 27% (trend significant between cycles 2 and 4, P = 0.004). Fifteen patients were re-treated with platinum after progression after PLD with 80% (12/15) of the patients responding. The RR to platinum retreatment after PLD compares favorably with the historical data on the response to second-line platinum retreatment. The sole use of early Ca125 trends in PLD treatment before cycle 4 may result in an erroneous discontinuation of PLD in potential responders. Retreatment with platinum after PLD may yield a good RR in selected patients even those with disease progression within 12 months after prior platinum treatment.

Phase I and Pharmacokinetic Study of 7-Hydroxystaurosporine and Carboplatin in Advanced Solid Tumors

Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules. Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m(2). Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 90 mg/m(2) in cycle 1, 45 mg/m(2) in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables C(max) and t(1/2) of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t(1/2) for cycle 1 was 506 +/- 301 h, and the mean C(max) for all dose levels was >30 micromol/L. The mean AUC over the dosing interval for each dose level ranged from approximately 6,000 to 9,000 micromol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion. The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted.

Lung Cancer

Lung Cancer

Phase II evaluation of a 3-day infusion of topotecan in patients with recurrent ovarian or primary peritoneal cancer

Objective. To assess the efficacy and toxicity profile in patients treated with topotecan at 2.0 mg/m 2/day × 3 days every 3 weeks. Materials and methods. Eligibility criteria included patients with recurrent primary peritoneal or epithelial ovarian cancer with ≥ 6 months elapsed from time of prior platinum treatment. Patients were required to have a performance status of ≤ 2 and normal hepatic and renal function. Response to therapy and toxicity was assessed using standard criteria. Chi-square and Student's t tests were used as appropriate. Survival was assessed with Kaplan–Meier method. Results. All 40 patients enrolled were assessable for response. The mean age of the patients was 63.2 years (range 43–85). Median time to progression from initial treatment was 11.8 months. A total of 286 cycles of chemotherapy were administered with an average of 7.1 cycles per patient. Overall median time to progression (TTP) with 3-day topotecan treatment was 21 weeks (range 6–43 weeks). Of the 33 patients with measurable disease, 24% (11–42%, 95% CI) demonstrated a response. Seven patients had CA-125 evaluable disease with a response of 43% (10–89%, 95% CI). Median progression-free survival (PFS) was 16 weeks (range 12–21 weeks, 95% CI). Median overall survival was 106 weeks (range 76–117 weeks, 95% CI). Assessment of toxicity by patient showed 90% demonstrating grade 3/4 neutropenia with the vast majority being uncomplicated. No severe non-hematological toxicity was observed. Conclusion. Administration of topotecan as a 3-day regimen is feasible with demonstrable activity and tolerable toxicity. Critical comparison to the 5-day regimen in a randomized fashion is warranted.