Hema Parmar

Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-mutant tumor patients with measurable disease [5/14: 4 breast cancer (3 patients at 12 mg); 1 non-small cell lung cancer], where responses started at 3 mg, and 0% in patients with tumors without known PIK3CA hotspot mutations (0/15).Significance: Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with PIK3CA-mutant tumors (in comparison with patients with tumors without known activating PIK3CA hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against PIK3CA-mutant tumors. Cancer Discov; 7(7); 704-15. ©2017 AACR.See related commentary by Rodon and Tabernero, p. 666This article is highlighted in the In This Issue feature, p. 653.

Abstract LB-64: GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study.

Background: GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3Kα, δ, and γ isoforms, with 30 fold less inhibition of the PI3K β isoform relative to the PI3Kα isoform. Preclinical data show that GDC-0032 has increased activity against PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. Methods: A Phase Ia, multicenter, open-label study was conducted to evaluate the safety and pharmacokinetics (PK) of GDC-0032 administered once daily in patients with locally advanced or metastatic solid tumors. Preliminary assessment of the anti-tumor activity of GDC-0032 was also performed. The study consisted of 3+3 dose-escalation cohorts with a 35-day window to evaluate dose-limiting toxicity (DLT). Results: As of August 1, 2012, 34 patients were enrolled in this study. Five dosing cohorts ranging from 3 to 16 mg QD were tested (3, 5, 8, 12, and 16 mg), and dose escalation has been completed. Two DLTs (Grade 4 hyperglycemia and Grade 3 fatigue) were observed in two patients from the 16 mg cohort. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, fatigue, nausea, decreased appetite, and vomiting. The only Grade 4 treatment-related AE (hyperglycemia) occurred in the 16 mg cohort. GDC-0032 PK was approximately dose proportional and time independent with a mean t1/2 of 40 hours. Paired pre-treatment and on-treatment tumor biopsies of a patient in the 3 mg cohort showed pharmacodynamic inhibition of the PI3K pathway as assessed by reverse phase protein array. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 7 out of 13 patients assessed (54%). Clinical partial responses (PRs) were observed in 5 patients treated at doses of GDC-0032 ranging from 3-12 mg QD. Consistent with GDC-0032 preclinical data, 3 PRs (2 confirmed) were observed out of 5 patients with PIK3CA mutant breast cancer (RECIST -30% to -70%). One cPR has been observed in a patient with PIK3CA mutant NSCLC, and 1 uPR in a patient with HER2-positive, PIK3CA wildtype, breast cancer. Conclusion: GDC-0032 is a PI3K inhibitor with dose-linear PK and expected in-class toxicities. Pharmacodynamic inhibition of the PI3K pathway has been observed in tumor biopsies and FDG-PET imaging. Clinical partial responses observed in patients with PIK3CA mutant and HER2+ tumors suggest that GDC-0032 may have increased anti-tumor activity in diagnostically defined subpopulations. Citation Format: Dejan Juric, Ian Krop, Ramesh K. Ramanathan, Jim Xiao, Sandra Sanabria, Timothy R. Wilson, YounJeong Choi, Hema Parmar, Jerry Hsu, Jose Baselga, Daniel D. Von Hoff. GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study. [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 LB-64. doi:10.1158/1538-7445.AM2013-LB-64

Abstract PD5-2: Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer

Background: Taselisib (GDC-0032) is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant (MT) cancers. Taselisib is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PI3K alpha isoform (PIK3CA) MT breast cancer cell lines and enhanced antitumor activity when combined with letrozole. Clinical data with single-agent taselisib also showed increased tumor shrinkage in patients with PIK3CA MT breast cancer as compared to patients with PIK3CA wildtype (WT) breast cancer. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of taselisib doses ranging from 6-9 mg QD in combination with letrozole 2.5mg QD in a modified 3+3 design. A dose expansion cohort was conducted with taselisib 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment by FDG-PET, and anti-tumor activity by RECIST. Results: As of 31 January 2014, 28 patients were enrolled onto this study with the completion of dose escalation and the dose expansion cohort. No dose limiting toxicities (DLTs) were observed at either the 6 mg (n = 20) or 9 mg (n = 8) dose levels. Adverse events (AEs) assessed by the investigator as related to taselisib in ≥10% of patients (any grade) included diarrhea, nausea, stomatitis, fatigue, rash, decreased appetite, hyperglycemia, dysgeusia, mucosal inflammation, vomiting, muscle spasms, asthenia, dry mouth, dry skin, pruritus, and aspartate aminotransferase increased. Grade 3 and 4 adverse events assessed by the investigator as drug-related and occurring in greater than one patient included diarrhea (14%), hyperglycemia (7%), and mucosal inflammation (7%). No apparent PK interactions were observed between taselisib and letrozole. The median number of prior systemic therapies was six, and promising efficacy data has been observed in these heavily pretreated patients. Metabolic partial responses via FDG-PET (≥ 20% decrease in mean SUVmax) were observed in 11 out of 18 patients assessed (61%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg taselisib dose levels. For patients with measurable disease at baseline, the overall response rate of 38% was observed in patients with PIK3CA MT breast cancer and 9% in patients with PIK3CA WT breast cancer. Updated data on safety, PD, efficacy, and biomarker correlates will be presented. Conclusions: The combination of taselisib and letrozole is a well-tolerated regimen with promising preliminary efficacy in PIK3CA MT breast cancer patients. This preliminary Ph1b clinical data is consistent with taselisib preclinical and single-agent clinical data showing increased anti-tumor activity for taselisib in PIK3CA MT breast cancer as compared to PIK3CA WT breast cancer. Taselisib is being further investigated in the neoadjuvant setting in combination with letrozole in the LORELEI study in patients with untreated hormone receptor-positive breast cancer. Citation Format: Cristina Saura, Jasgit Sachdev, Manish R Patel, Andres Cervantes, Dejan Juric, Jeffrey R Infante, Donald Richards, Sandra Sanabria, Xuyang Lu, Joseph Ware, Timothy R Wilson, Hema Parmar, Jerry Y Hsu, Mafalda Oliveira, Eric P Winer, Daniel D Von Hoff, Jose Baselga, Ian E Krop. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer [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 PD5-2.

A multicenter, single-arm, open-label, phase 2 study of apitolisib (GDC-0980) for the treatment of recurrent or persistent endometrial carcinoma (MAGGIE study).

The current single‐arm, open‐label trial was designed to evaluate the activity of apitolisib (GDC‐0980), a dual phosphoinositide 3‐kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, in patients with advanced endometrial cancer (EC).

Abstract PD1-3: Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer

Background: GDC-0032 is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that GDC-0032 has enhanced activity against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines. Preclinical data also show enhanced antitumor activity when GDC-0032 is combined with fulvestrant. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of GDC-0032 doses ranging from 6-9 mg QD in combination with fulvestrant 500mg q4wk (with loading dose of 500mg at day 1, 14 and 28) in a modified 3+3 design. A dose expansion cohort was conducted at the recommended Phase 2 dose of 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment of PI3K pathway inhibition by paired tumor biopsies and by FDG-PET, and anti-tumor activity by RECIST. Results: As of 1 Mar 2013, 17 patients were enrolled onto this study with the completion of dose escalation. No dose limiting toxicities (DLTs) were observed at either the 6 mg or 9 mg dose levels. Adverse events (AEs) assessed by the investigator as related to GDC-0032 in ≥10% of patients, were diarrhea, hyperglycemia, stomatitis, fatigue, asthenia, decreased appetite, nausea, mucosal inflammation and rash. No observed apparent PK interactions were observed between GDC-0032 and fulvestrant. The median number of prior systemic therapies was 6. Metabolic partial responses via FDG-PET (≥ 20% decrease in mSUVmax) were observed in 8 out of 11 patients assessed (73%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg GDC-0032 dose levels. These include patients who have had prior treatment with fulvestrant. As of 29 May 2013, enrollment onto the dose escalation and expansion cohort has been completed (n = 27). Updated data on safety, pharmacodynamics, efficacy, and biomarker correlates will be presented. Conclusions: The combination of GDC-0032 and fulvestrant is a well-tolerated regimen with promising preliminary efficacy. GDC-0032 is being further investigated in combination with fulvestrant for patients with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-3.

Abstract OT1-1-01: LORELEI: A Phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer

Background: Taselisib (GDC-0032) is an orally bioavailable, potent, and selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have also demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer treated with single-agent taselisib. Preclinical and clinical data also show enhanced antitumor activity when taselisib is combined with either letrozole or fulvestrant. Study design: LORELEI is a phase II, two-arm, randomized, double-blind, multicenter, neoadjuvant study of letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, stage I-III operable breast cancer. Other relevant eligibility criteria include tumor size ≥ 2 cm, unilateral disease, ECOG PS ≤1, and available and evaluable tumor tissue for central review of PIK3CA mutation analysis. Patients will be randomized (1:1) to receive continuous daily letrozole (2.5 mg) with either placebo or taselisib (4mg on a 5 days on/ 2 days off schedule) for 16 weeks. Study treatment is followed by surgery. Adjuvant treatment will be given as per physician’s discretion. Stratification at randomization is based on tumor size and nodal status. Endpoints: The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast magnetic resonance imaging (MRI) via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all enrolled patients and PIK3CA mutant (MT) patients. Secondary endpoints include ORR by centrally assessed MRI and pCR rate in PIK3CA wild-type (WT) patients. Other secondary endpoints performed in all enrolled patients and separately as per PIK3CA mutation status include: assessment of ORR using breast ultrasound, clinical breast exam (i.e. palpation) and mammography; changes in Ki67 levels from baseline to week 3, baseline to surgery and week 3 to surgery; centrally assessed preoperative endocrine prognostic index (PEPI) score; changes in enhancing tumor volume from baseline to surgery as measured by breast MRI via central assessment. Exploratory analyses include expression of biomarkers predictive of response to letrozole plus taselisib from tumor tissue or blood. Statistical methods: The sample size was calculated to detect an absolute percentage increase of 24% in ORR via MRI (40% in the letrozole-placebo arm vs. 64% in the letrozole-taselisib arm in the PIK3CA MT cohort) with 80% power at 16% two-sided significance level. The sample size will also detect an absolute percentage increase of 18% in pCR rate (1% in the letrozole-placebo arm vs 19% in the letrozole-taselisib arm in the PIK3CA MT cohort) with 80% power at 4% two-sided significance level. Target accrual: Approximately 330 pts at 110 global sites across Europe, North and South America, and Asia-Pacific. Reference Study ID Numbers: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38. Citation Format: Cristina Saura, Evandro de Azambuja, Peter Dubsky, Mafalda Oliveira, Kamal S Saini, Christian Fes, Ray S Lin, Timothy R Wilson, Jill Fredickson, Hema Parmar, Jerry Y Hsu, Martine Piccard, Michael Gnant, Jose Baselga. LORELEI: A Phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer [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 OT1-1-01.

Abstract A03: Comprehensive predictive biomarker evaluation in two phase II clinical trials of the PI3K/mTOR inhibitor GDC-0980 in metastatic renal cell carcinoma and advanced endometrial cancer

Background: The PI3K/mTOR pathway is frequently activated in cancer by multiple mechanisms. GDC-0980 is a dual pan-PI3K and mTOR (TORC1/2) inhibitor that has been evaluated in two Phase II studies (J Clin Oncol 32:5s, 2014 [suppl; abstr 4525 and 5513]). The randomized ROVER study showed that the PI3K/mTOR inhibitor GDC-0980 did not improve efficacy over the TORC1 inhibitor everolimus in metastatic renal cell carcinoma (mRCC). The single arm MAGGIE study evaluated the activity of GDC-0080 in patients with advanced endometrial cancer (EC). Although some single agent anti-tumor activity was observed, overall evaluation of anti-tumor activity of GDC-0980 was limited by tolerability, especially in diabetic patients. Comprehensive biomarker analysis, including targeted next generation sequencing (NGS) and a panel of biomarkers tailored to each tumor type, was conducted in both Phase II studies to determine the prevalence of PI3K/mTOR pathway alterations, and to assess the association between anti-tumor activity and candidate predictive biomarkers. Methods: The primary and secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). Archival tissue samples were collected for biomarker analysis, and correlations with efficacy were retrospectively explored. Samples were subjected to targeted NGS (Illumina) covering 88 oncogenes and tumor suppressors, copy number analysis using quantitative-PCR, PTEN immunohistochemistry (IHC), HIF1A IHC (ROVER), and gene expression analysis (NanoString nCounter® System, ROVER). Results: In ROVER, the median PFS was significantly shorter for GDC-0980 than everolimus. Retrospective biomarker analyses revealed a relationship between VHL mutation status (by NGS) and improved PFS with everolimus but not GDC-0980. High HIF1A protein expression was associated with longer PFS in both arms, whereas low expression of STK11/LKB1 mRNA was associated with benefit with everolimus only. Additional gene expression analysis of PI3K pathway, apoptosis/cell cycle, and tumor immunity related genes will be presented. In MAGGIE, PFS at 6 months was estimated to be 20%, and the ORR was 9% (unconfirmed). Evaluable archival tumor samples were obtained from 88% of the patients and 52% of patients had at least one alteration in PIK3CA, PTEN or AKT1. PTEN loss by IHC was generally well correlated with mutation status determined by NGS. All 5 patients with either a confirmed or investigator assessed partial response had at least one PI3K pathway alteration. Conclusions: Clinical data to date have suggested that identification of predictive biomarkers for agents targeting PI3K/mTOR signaling is challenging and will require tailoring to specific tumor types. Here we provide comprehensive assessment from two phase II clinical studies of GDC-0980. Our data, although retrospective in nature and requiring confirmation, suggest that pathway activation along the VHL-HIF1A axis may be predictive of anti-tumor activity for mTOR-targeting agents in mRCC. Our results in EC suggest that at least in this study population, frequency of pathway alterations was somewhat lower than observed in prior published data, but the presence of PIK3CA or AKT1 mutations or PTEN loss enriched for anti-tumor activity. Clinical trial information: NCT01442090 (mRCC), NCT01455493 (EC). Citation Format: Jill M. Spoerke, Vicky Makker, Carol Aghajanian, Powles Thomas, Robert J. Motzer, Jennifer O. Lauchle, Hema Parmar, Houston Gilbert, Wei Lin, Bridget O9Keeffe, Michelle Byrtek, Hartmut Koeppen, Yulei Wang, Shan Lu, Ling-Yuh Huw, Garret M. Hampton, Mark R. Lackner. Comprehensive predictive biomarker evaluation in two phase II clinical trials of the PI3K/mTOR inhibitor GDC-0980 in metastatic renal cell carcinoma and advanced endometrial cancer. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A03.

Abstract 2399: Circulating tumor DNA (ctDNA) analysis of PIK3CA and AKT1 mutations in patients enrolled onto the Phase 1b study of the PI3K inhibitor taselisib (GDC-0032) in solid malignancies

The PI3K signaling pathway is one of the most frequently activated pathways in cancer, and controls critical proliferative and survival processes. Taselisib (GDC-0032) is a novel, oral, selective inhibitor of PI3K, sparing inhibition of PI3Kβ. (Ndubaku CO et al. J Med Chem 2013). Preclinically, taselisib demonstrates enhanced potency in PIK3CA mutant cells, with greater signaling and growth/survival effects in mutant cells vs. wild-type cells. In the phase Ia study with single agent taselisib, partial responses (PRs) were observed in 6/34 enrolled patients. All 6 responses were observed in patients with PIK3CA mutant tumors (Juric D. et al. AACR 2013), indicating the need to determine PIK3CA mutation status from patients treated with taselisib. Circulating tumor DNA (ctDNA) provides an up-to-date liquid biopsy that can be used to detect somatic mutation in oncogenes especially when tumor tissue is not available. Analysis was undertaken on five cohorts of patients enrolled onto the taselisib Phase 1b study comprised of 106 patients. In total, 87 patients had tumor tissue available for PIK3CA mutation testing. Plasma was collected from 91 patients prior to treatment and 10 patients had matched plasma collected at the study discontinuation visit. Tissue samples were assessed using the Roche cobas PIK3CA mutation test that detects 17 PIK3CA hotspot mutations, of which 47 (54%) tissue samples were positive for PIK3CA mutations. Analysis of PIK3CA and AKT1 mutations from plasma was performed using an Inostics BEAMing digital PCR Oncobeam panel, which detects 8 PIK3CA hotspot mutations and 1 AKT1 mutation. ctDNA was detected in all 91 patients sampled, and ranged from 1.3ng to 1ug per milliliter of plasma. PIK3CA mutations were identified in the plasma of 51 patients (56%), and an AKT1 mutation was identified in one patient. For 80 patients that had both tissue and plasma available for PIK3CA mutation testing, a sensitivity of 81%, a specificity of 74% and an overall accuracy of 78% was observed. Allele frequency ranged from 0.02% to 75.58% with a median of 2.72%. In two cohorts that enrolled hormone receptor positive, HER2 negative breast cancer patients, a sensitivity of 84%, a specificity of 87% and an overall accuracy of 88% was observed between 42 matched tissue and plasma samples. In a patient who experienced a sustained clinical partial response to taselisib in combination with fulvestrant, a decrease in plasma PIK3CA allele frequency was observed from 3.05% in the pretreatment sample to 0.14% in the study discontinuation sample. In summary, analysis of PIK3CA mutations from plasma in patients enrolled onto trials testing the efficacy of taselisib may be a useful surrogate for patients when tissue is unavailable, an observation that is being assessed in ongoing trials. Citation Format: Timothy R. Wilson, Heidi Savage, Junko Aimi, Jessica Jin, Hema Parmar, Jerry Hsu, Ian Krop, Cristina Saura, Andres Cervantes, Jasgit Sachdev, Manish Patel, Juan Cejalvo, Mafalda Oliveira, Eric Winer, Daniel Von Hoff, Jose Baselga, Dejan Juric. Circulating tumor DNA (ctDNA) analysis of PIK3CA and AKT1 mutations in patients enrolled onto the Phase 1b study of the PI3K inhibitor taselisib (GDC-0032) in solid malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2399. doi:10.1158/1538-7445.AM2015-2399