Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors

Hyman, David M.; Snyder, Alexandra; Gerecitano, John F.; Voss, Martin H.; Ho, Alan L.; Konner, Jason; Winkelmann, J.; Stasi, Megan; Monson, Kelsey R.; Iasonos, Alexia; Spriggs, David R.; Bialer, Philip; Lacouture, Mario E.; Teitcher, Jerrold B.; Katabi, Nora; Fury, Matthew G.

doi:10.1007/s00280-015-2693-z

Cited by 21 publications

(19 citation statements)

References 27 publications

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“…This latter statement is supported by the increased cytotoxicity observed in tumor cells of different origins to chemotherapy agents such as microtubule-targeting drugs (paclitaxel, docetaxel and vinblastine) [115], topotecan [116], cisplatin [117], and doxorubicin [118], when treatment was combined with inhibitors of components of PI3K/Akt pathway. Likewise, early evidence of antitumor activity, induced by either inhibiting Akt using MK-2206 [119] plus carboplatin and paclitaxel, docetaxel, or erlotinib, or inhibiting PI3K using the pan-class 1A PI3K inhibitor BKM120 [120] plus carboplatin and paclitaxel in patients with different solid tumors, supports the above-described role for PI3K/Akt in resistance to chemotherapy agents [119,120].…”

Section: Importance Of Akt In Radiotherapy Resistancementioning

confidence: 71%

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

Toulany

Rodemann

2015

Seminars in Cancer Biology

140

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Section: Importance Of Akt In Radiotherapy Resistancementioning

confidence: 71%

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

Toulany

Rodemann

2015

Seminars in Cancer Biology

140

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“…Two studies have evaluated BKM120 with paclitaxel or paclitaxel/carboplatin [11, 13]. In both studies, the MTD of BKM120 was the same as the single-agent MTD (100 mg daily) and the combination was reported to be well tolerated.…”

Section: Discussionmentioning

confidence: 99%

“…Dose limiting toxicity (DLT) included hyperglycemia, skin rash, epigastric pain, and mood disorders. Two subsequent studies have confirmed that BKM120 is well tolerated when combined with both the aromatase inhibitor letrozole in estrogen receptor-positive metastatic breast cancer and carboplatin plus paclitaxel in advanced solid tumors [11, 12]. Based on the above rationale, we conducted a phase I trial of BKM120 in combination with mFOLFOX6 in order to determine the MTD of the combination in patients with refractory advanced solid tumors.…”

Section: Introductionmentioning

confidence: 99%

A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors

et al. 2015

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Summary Purpose The oral PI3K inhibitor BKM120 has been reported as safe and well tolerated in early phase clinical trials of advanced cancer patients. We performed a phase I trial of BKM120 plus mFOLFOX6 (5-FU/LV + oxaliplatin), a common chemotherapeutic backbone in GI malignancies, to establish the maximum tolerated dose (MTD) and characterize the safety and tolerability of the combination. Methods Patients with advanced solid tumors received oral BKM120 daily combined with standard doses of mFOLFOX6 every 2 weeks of a 28 day cycle. The study utilized a standard 3 + 3 dose escalation schema. Results A total of 17 patients received treatment with BKM120, 13 of which were evaluate for dose limited toxicity (DLT). The most common tumor types were colorectal cancer, cholangiocarcinoma, pancreatic cancer and hepatocellular carcinoma. DLT included grade 3 hyperglycemia, grade 3 AST/ALT elevation, grade 4 neutropenia and grade 4 thrombocytopenia. A total of 76 % of patients experienced treatment related grade 3/4 adverse events (AEs), the most common of which were neutropenia, fatigue, leukopenia, hyperglycemia and thrombocytopenia. One patient demonstrated an unconfirmed partial response and three patients had stable disease. Discussion The MTD of BKM120 in combination with standard doses of mFOLFOX6 was 40 mg daily, which is well below the 100 mg daily dose proven effective and tolerable both as a single agent and in combination with other chemotherapeutics. In addition, the regimen of BKM120 with mFOLFOX6 in patients with refractory solid tumors resulted in increased toxicity than would be expected from either the PI3K inhibitor or the chemotherapy backbone alone.

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“…We established the MTD/recommended phase II dose (RP2D) for the combination and reported that the addition of buparlisib to q3 weeks carboplatin (AUC 5) and paclitaxel (175 mg/m2) was well tolerated and permitted full dosing of buparlisib (100 mg/daily) compared with the alternate q4 weeks carboplatin (AUC 5) and paclitaxel schedule of 80 mg/m2 (days 1, 8, and 15) that limited buparlisib escalation to 80mg/day. [18] Additive clinically significant myelosuppressive effects were not seen with the q3 weeks combination. In view of the favorable safety profile seen with the combination in the q3 week schedule, we sought to explore a higher dose of this regimen in an expansion cohort.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, we also observed in the dose escalation study, promising activity against tumors with loss of PTEN expression. [18] An observation with some mechanistic rationale, given PTEN deficient tumors are dependent on p110β PI3K signaling and buparlisib having activity against this isoform, is potentially desirable for these tumors. [19,20] Indeed pre-clinical studies have shown synergistic lethality with the combination of buparlisib and platinum-based chemotherapy in PTEN deficient xenografts.…”

Section: Introductionmentioning

confidence: 99%

A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel

et al. 2017

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Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n=5 [71%]), hyperglycemia (n=2, [29%]), diarrhea (n=2, [29%]) and rash (n=2, [29%]) and in cohort B included lymphopenia (n=5 [71%]), hyperglycemia (n=4 [57%]) and neutropenia (n=2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2/14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors,

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Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors

Abstract: The addition of buparlisib to carboplatin + paclitaxel was well tolerated, and preliminary activity was notable against tumors with loss of PTEN expression.

Cited by 21 publications

References 27 publications

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

A phase I trial of mFOLFOX6 combined with the oral PI3K inhibitor BKM120 in patients with advanced refractory solid tumors

A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel

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