Outcome of BRCA 1/2-mutated (BRCA+) and triple-negative, BRCA wild type (BRCA-wt) breast cancer patients in a phase I study of single-agent veliparib (V).

2014 ◽  
Vol 32 (26_suppl) ◽  
pp. 135-135 ◽  
Author(s):  
Shalu Pahuja ◽  
Jan Hendrik Beumer ◽  
Leonard Joseph Appleman ◽  
Hussein Abdul-Hassan Tawbi ◽  
Ronald G. Stoller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Triple Negative ◽  
Single Agent ◽  
Parp Inhibitors ◽  
Maximum Tolerated Dose ◽  
Serous Ovarian Cancer ◽  
Number Of Patients

135 Background: Veliparib (V) (ABT-888) is an oral, potent inhibitor of PARP 1/2. PARP inhibitors have preclinical and clinical efficacy in BRCA+ malignancies. There are genotypic and phenotypic similarities between BRCA+ cancers, serous ovarian cancer and basal-like breast cancer and we postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose -limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed V in 2 cohorts of patients, BRCA+ and BRCA-wt (consisting of serous ovarian cancer and triple-negative breast cancer (TNBC). Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID to determine a maximum tolerated dose (MTD) and recommended phase II dose (RP2D). V was administered orally continuously on a 28 day cycle. BRCA+ and BRCA-wt patients were enrolled in 2 separate cohorts with 2 separate escalations. Results: 98 (70 BRCA+ and 28 BRCA-wt) pts have been enrolled. The maximum administered dose (MAD) was 500mg BID and the MTD/RP2D is 400mg BID for both cohorts. 59 BRCA+ pts and 24 BRCA-wt pts (21 TNBC and 3 ovary) were evaluable for response. ORR was defined as CR+PR and clinical benefit rate (CBR) as CR+PR+SD > 6 months. Results are summarized in the table. Conclusions: There is evidence of anti-tumor activity with V comparable to that of other PARP inhibitors in the BRCA+ population. There was indication of dose responsiveness with greater activity in this population at higher doses. There is less activity in the mostly TNBC, BRCA-wt population, although there was evidence of benefit in a small number of patients. Ongoing tissue correlative studies will help to identify potential mechanisms of sensitivity and resistance. Clinical trial information: NCT00892736. [Table: see text]

First-in-human phase I/Ib multicenter, open-label dose escalation study to assess safety and tolerability of PMD-026 in patients with metastatic breast cancer with expansion in metastatic triple negative breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Muralidhar Beeram ◽  
Judy Sing-Zan Wang ◽  
Lida A. Mina ◽  
Amita Patnaik ◽  
Mary Rose Pambid ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Triple Negative Breast Cancer ◽  
Dose Escalation ◽  
Triple Negative ◽  
Single Agent ◽  
Metastatic Breast ◽  
Open Label

TPS1110 Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited durable treatment options. RSK (P90 ribosomal S6 kinase) is a signaling protein at the convergence point of PDK-1 and MAPK signaling pathways. RSK1-3 phosphorylates transcription factors, including Y-box binding protein-1 (YB-1), thereby inducing drug resistance and cancer growth genes. Phosphorylated YB-1 is involved in tumor cell survival, proliferation, and drug resistance. In human breast tumor samples, RSK2 protein is expressed across all breast cancer subtypes (TNBC, ER+ and HER2+) and is associated with poor overall survival. Expression of RSK2 is found in approximately 87% of mTNBC tumors and of those tumors approximately 41% have very high expression of RSK2. PMD-026 is a potent, oral, small molecule RSK inhibitor with high selectivity for RSK2. Preclinical in vivo studies have demonstrated activity both as a single agent and in combination with standard of care therapies. Further, a CAP/CLIA certified IHC method has been developed with Roche to determine tumor expression of RSK2. Methods: This single-arm, open-label, first-in-human, phase I/Ib study evaluates the safety and efficacy of single agent PMD-026 in patients with metastatic breast cancer for whom standard therapies are no longer effective. During dose escalation, the study utilizes an accelerated titration design with single patient cohorts until the occurrence of DLT or Grade 2+ toxicity; then reverts to 3+3 design to define the maximally tolerated dose (MTD) and recommended phase II dose (RP2D). The dose expansion portion will enroll approximately 20 patients with mTNBC. Patients are dosed orally once daily in 21-day cycles with measures to adapt the dosing schedule based on the pharmacokinetic (PK) data, as needed. Tumor tissue is required for all enrolled patients; RSK2 expression will be retrospectively correlated with clinical outcomes. The primary objectives are to determine safety and tolerability of PMD-026, determine the MTD, define a RP2D, and assess anti-tumor activity of PMD-026 in patients with TNBC. Secondary objectives are to evaluate PK, time to response, mTNBC subtyping using NanoString, and duration of response of PMD-026. To date, cohorts 1 and 2 have been completed without DLT. Enrollment to cohort 3 began in January 2020. Clinical trial information: NCT04115306 .

A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA+), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
Shannon Leigh Huggins-Puhalla ◽  
Jan Hendrik Beumer ◽  
Leonard Joseph Appleman ◽  
Hussein Abdul-Hassan Tawbi ◽  
Ronald G. Stoller ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Methylation Status ◽  
Single Agent ◽  
Parp Inhibition ◽  
Low Grade ◽  
Basal Like Breast Cancer ◽  
Dose Levels

3054 Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2. Preclinically, PARP inhibitors have activity in tumors with defective homologous recombination (HR), particularly those that are BRCA+. Reduced levels of BRCA expression have been observed in ovarian cancer and basal-like breast cancer, which share genotypic and phenotypic similarities with BRCA+ cancers. We postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed veliparib. Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID. Veliparib was administered orally continuously on a 28 day cycle. Results: 63 pts have been enrolled to date. Thirty-eight were BRCA+ (20 ovary, 12 breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube, endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the following dose levels: BRCA+: gr. 2 thrombocytopenia at 50 mg BID; BRCA+: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at 400 mg BID. The MTD has not been determined and 500 mg BID is presently enrolling. Notable toxicities have included low-grade fatigue and nausea. PK was linear and non-saturable with t ½ of 5 h. The number of cycles administered ranged from 1- 15, median 2. In BRCA+ pts, there were 2 partial responses (breast, ovarian) and 10 pts had evidence of prolonged SD ≥ 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7 pts with SD≥ 4 months. Correlative studies, including assessment of PAR inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib is tolerable on a continuous oral dosing schedule with evidence of anti-tumor activity seen in BRCA+ and BRCA-wt tumors. A mandatory biopsy expansion cohort is planned at the recommended phase II dose, which will allow further insights regarding efficacy and mechanisms of resistance to PARP inhibition.

Phase I study of oral BKM120 and oral olaparib for high-grade serous ovarian cancer (HGSC) or triple-negative breast cancer (TNBC).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2510-2510 ◽  
Author(s):  
Ursula Matulonis ◽  
Gerburg M. Wulf ◽  
Michael J. Birrer ◽  
Shannon Neville Westin ◽  
Philippa Quy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Phase I ◽  
Triple Negative Breast Cancer ◽  
Phase I Study ◽  
Triple Negative ◽  
High Grade ◽  
Serous Ovarian Cancer

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

1996 ◽  
Vol 14 (12) ◽  
pp. 3074-3084 ◽  
Author(s):  
E K Rowinsky ◽  
S H Kaufmann ◽  
S D Baker ◽  
L B Grochow ◽  
T L Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
In Vitro Studies ◽  
Pharmacokinetic Studies ◽  
Sequence Dependence ◽  
Renal Tubular

PURPOSE A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Phase I trial of escalating doses of weekly everolimus (RAD001) in combination with docetaxel for the treatment of metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1066-1066
Author(s):  
S. L. Moulder ◽  
E. Rivera ◽  
J. Ensor ◽  
A. Gonzalez-Angulo ◽  
M. Christofanilli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Metastatic Breast ◽  
Maximum Tolerated Dose ◽  
Entire Group ◽  
Interpatient Variability ◽  
Grade 3

1066 Background: Inhibition of mTOR with everolimus (E) may improve efficacy in combination with docetaxel (D), but both drugs are metabolized by CYP3A4, thus a pharmacokinetic (PK) interaction may also exist. Methods: 15 patients (pts) with MBC were treated with docetaxel and everolimus using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). Docetaxel doses were 40–75 mg/m2 IV on day 1 of a 21 day cycle. Everolimus doses were 20–50 mg PO on days 1 and 8 of a 21 day cycle (except cycle 2, where only day 8 was given to allow single agent PK analyses of both drugs). Response was measured every 2 cycles using RECIST. Results: Median age= 58 years and 77% of pts had >2 prior chemotherapies for MBC. Initially 2 of 2 pts treated (D= 75 mg/m2, E= 30 mg) developed DLT (neutropenic fever/infection), prompting a mandatory PK evaluation for all pts enrolled in subsequent cohorts. A second cohort of 3 patients (D=60 mg/m2, E=20mg) had no DLT, but no pts received day 8 of E due to grade 3–4 neutropenia. PK analyses demonstrated a 42% lowered (-42%) D clearance at the 60 mg/m2 in the presence of E (n=1). Subsequent cohorts were accrued at D=40 mg/m2 with escalating doses of E (Table). For the entire group, an 18% decrease (-18%) in D clearance was observed when D was administered concomitantly with E. High interpatient variability of D clearance was observed (range +16% to -135%). No pts had CR/PR, but 6 had SD>4 cycles and 2 had SD=8 cycles. Conclusions: Weekly everolimus appears to cause widely variable and unpredictable changes in docetaxel clearance making this combination unfeasible. [Table: see text] No significant financial relationships to disclose.

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