Damien M. Cronier

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial

BACKGROUND Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. METHODS We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. FINDINGS 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 μg/mL (CV% 33.0) and from 123 μg/mL (CV% 31.2) to 156 μg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients). INTERPRETATION This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma. FUNDING Eli Lilly and Company.

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors.

UNLABELLED We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months. SIGNIFICANCE Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53. ©2016 AACR.See related commentary by Lim et al., p. 697This article is highlighted in the In This Issue feature, p. 681.

Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts

Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors. Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts. Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations. Conclusions: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies. Clin Cancer Res; 20(14); 3763–74. ©2014 AACR.

Results of a Phase 1 Study of AME-133v (LY2469298), an Fc-Engineered Humanized Monoclonal Anti-CD20 Antibody, in FcγRIIIa-Genotyped Patients with Previously Treated Follicular Lymphoma

Purpose: AME-133v is a humanized monoclonal antibody engineered to have increased affinity to CD20 and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) better than rituximab. Safety, pharmacokinetics, and efficacy were assessed in a phase 1/2 trial in patients with previously treated follicular lymphoma (FL). Patients and Methods: AME-133v was characterized in vitro by ADCC and cell binding assays. A phase 1 study was conducted in which 23 previously treated patients with FL were assigned sequentially to one of five dose-escalation cohorts of AME-133v at 2, 7.5, 30, 100, or 375 mg/m2 weekly × 4 doses. Results: AME-133v showed a 13- to 20-fold greater binding affinity for CD20 and was 5- to 7-fold more potent than rituximab in ADCC assays. Cell binding assays showed AME-133v and rituximab competed for an overlapping epitope on the CD20 antigen, and AME-133v inhibited binding of biotinylated rituximab to CD20 in a concentration-dependent manner. AME-133v was well tolerated by patients and common related adverse events included chills and fatigue. One patient experienced a dose-limiting toxicity of neutropenia. AME-133v showed nonlinear pharmocokinetics with properties similar to rituximab. Selective reduction of B cells during and after AME-133v treatment was shown by flow cytometry of peripheral blood. A partial or complete response was observed in 5 of 23 (22%) patients and the median progression-free survival was 25.4 weeks. Conclusions: AME-133v was safe and well tolerated at the doses tested. AME-133v showed encouraging results as an anti-CD20 therapy in heavily pretreated FL patients with the less favorable FcγRIIIa F-carrier genotype. Clin Cancer Res; 18(5); 1395–403. ©2012 AACR.

Abstract CT232: Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer

LY2835219 is a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), which act in a protein complex with D-type cyclins to enable G1 to S cell cycle progression. Preclinical models indicate this complex plays a critical role in breast cancer. We conducted a phase I study with expansion cohorts to evaluate the safety, pharmacokinetics, and antitumor activity of LY2835219 in 5 different tumor types: glioblastoma; melanoma; and cancers of the lung, colon/rectum and breast. In the expansion cohorts, LY2835219 was administered continuously at 150-200mg orally every 12 hours on Days 1-28 of a 28-day cycle. RECIST v1.1 was used to assess tumor response. The most common possibly related treatment-emergent adverse events across the expansion cohorts (n=132) included diarrhea (5% G3/4), nausea (3% G3/4), fatigue (2% G3/4), vomiting (2% G3/4) and neutropenia (11% G3/4). In the metastatic breast cancer (MBC) cohort, 47 patients with a median of 7 prior systemic regimens received therapy with LY2835219. Across all MBC patients, 9 achieved a best overall response of confirmed partial response (PR), 24 achieved stable disease (SD), 11 had progressive disease (PD), and 3 were not evaluable for response. Among the 36 HR+ patients, there were 9 confirmed partial responses for an ORR of 25%. In addition, 20 of these 36 HR+ patients (56%) had SD: 7 patients had SD Citation Format: Amita Patnaik, Lee S. Rosen, Sara M. Tolaney, Anthony W. Tolcher, Jonathan W. Goldman, Leena Gandhi, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew W. Rasco, Scott P. Myrand, Palaniappan Kulanthaivel, Lily Li, Martin Frenzel, Damien M. Cronier, Edward M. Chan, Keith T. Flaherty, Patrick Y. Wen, Geoffrey I. Shapiro. Clinical activity of LY2835219, a novel cell cycle inhibitor selective for CDK4 and CDK6, in patients with metastatic breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT232. doi:10.1158/1538-7445.AM2014-CT232

A Novel CDK9 Inhibitor Shows Potent Antitumor Efficacy in Preclinical Hematologic Tumor Models

DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies. Mol Cancer Ther; 13(6); 1442–56. ©2014 AACR.

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma

Patients with follicular lymphoma (FL), where position 158 of FcγR‐IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F‐carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F‐carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody‐dependent cell‐mediated cytotoxicity. This dose‐escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20‐positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m2 weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F‐carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose‐limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F‐carriers. Further investigation of FL is warranted. (Cancer Sci 2011; 102: 432–438)

Phase 1/2 Study of Ocaratuzumab, an Fc-Engineered Humanized Anti-CD20 Monoclonal Antibody, in Low-Affinity FcγRIIIa Patients with Previously Treated Follicular Lymphoma

Abstract This phase 2 study assessed the safety and efficacy of ocaratuzumab, a humanized anti-CD20 monoclonal antibody. Fifty patients with previously treated follicular lymphoma (FL) and a low-affinity genotype of FcγRIIIa received ocaratuzumab 375 mg/m2 weekly for 4 weeks. Grade 3/4/5 adverse events (AEs) were reported in 11/1/1 patients, respectively. Serious AEs were reported by 11/50 patients, and three discontinued due to AEs. One patient died from aspiration pneumonia due to possibly drug-related nausea and vomiting. Investigator-assessed response rate was 30% (15/50), including four complete responses (CR), three CR unconfirmed (CRu) and eight partial responses (PR). Investigator-assessed median Progression-free survivial (PFS) was 38.3 weeks. Ocaratuzumabs pharmacokinetic profile was similar to that reported for rituximab. Lymphocyte subset analysis showed significant, selective reduction of B-cells during and after ocaratuzumab treatment. Ocaratuzumab at this dose and schedule is active and well tolerated in patients with previously treated FL with low affinity FcγRIIIa genotypes. ClinTrials registry number: NCT00354926.

Abstract B233: Identification and characterization of LY2835219: A potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6) with broad in vivo antitumor activity.

Dysregulation of the cell cycle, which normally regulates cell proliferation in response to mitogenic signaling and other extracellular stimuli, is a hallmark of cancer. The G1 restriction point is a primary mechanism controlling cell cycle progression and is controlled by the CDK4/6 pathway (CDK4/6-cyclin D1-Rb-CDKN2). The importance of this pathway is highlighted by inactivation of restriction point control in a majority of human tumors. Transition through the restriction point requires phosphorylation of Rb by CDK4/6, and these kinases are considered highly validated cancer drug targets. We have identified and characterized a potent and selective dual CDK4/6 inhibitor, LY2835219. Preclinical characterization was performed with the monomesylate salt (LY2835219-MsOH), which inhibits these kinases with a IC50 of 2 and 10 nM for CDK4 and CDK6, respectively. In vitro, LY2835219-MsOH is a potent inhibitor of Rb phosphorylation resulting in a G1 arrest, and its activity is specific for tumors that have functional Rb protein. In a multiplexed in vivo target inhibition assay (IVTI), LY2835219-MsOH is a potent inhibitor of Rb phosphorylation and induces complete cell cycle arrest 24 hrs after a single dose. In tumor-bearing mice, oral administration of LY2835219-MsOH inhibits tumor growth in a dose-dependent manner in colon (colo-205), glioblastoma (U87MG), acute myeloid leukemia (MV4–11), mantle cell lymphoma (Jeko-1), and lung (H460) xenografts. LY2835219-MsOH may be administered up to 56 days without adverse events or tumor outgrowth. LY2835219-MsOH enhances the in vivo activity of cytotoxic drugs, suggesting that this novel CDK4/6 inhibitor can be used in combination with these anti-neoplastic agents. In summary, we have identified an oral small molecule inhibitor of CDK4/6 that may provide therapeutic benefit to cancer patients with tumors that have functional Rb protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B233.

Abstract P5-19-13: Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer

Background: Abemaciclib, a small molecule inhibitor with selectivity against cyclin-dependent kinases 4 and 6 (CDK4/6), induces G1 arrest in Rb-proficient human breast cancers. In an early phase clinical trial, the safety and antitumor activity of abemaciclib (LY2835219) were evaluated in 2 cohorts of patients with metastatic breast cancer (mBC). One cohort evaluated single-agent abemaciclib in an unselected population of patients with mBC [Part D], while the combination of abemaciclib plus fulvestrant was evaluated in patients with hormone receptor positive (HR+) mBC [Part G]. We previously reported early results for these 2 cohorts of patients with mBC treated with either single-agent abemaciclib or the combination of abemaciclib plus fulvestrant (Patnaik et al, ASCO 2014). In the single-agent cohort, 47 patients with previously treated mBC were enrolled (36 HR+). All patients with >30% tumor reduction had HR+ mBC (13 of 36 patients). In this group of 13 patients with HR+ mBC, 9 patients had confirmed response for an objective response rate of 25%, and 4 patients had unconfirmed response. This study was ongoing with 14 of 36 HR+ mBC patients on treatment at time of analysis (range 238-471 days). Patients continuing on single-agent abemaciclib included 4 patients with unconfirmed response and 6 patients with confirmed response. For the combination of abemaciclib plus fulvestrant, 18 patients with HR+ mBC enrolled and 13 patients (72%) were still on treatment (range 31-143 days) at the time of analysis. Methods: In the single-agent cohort, patients with mBC were treated with abemaciclib at 150 or 200mg orally every 12 hours on a continuous schedule. In the combination cohort, patients with HR+ mBC (n=18) were treated with the combination of abemaciclib plus fulvestrant. Patients received abemaciclib at 200mg orally every 12 hours on a continuous schedule. Patients also received fulvestrant at 500mg intramuscularly every month. NCI CTCAE v4.0 was used to grade adverse events (AEs) and RECIST v1.1 was used to assess tumor response. Results: In the single-agent cohort, patients began enrolling in May 2012 with the last patient enrolled in March 2013. Patients had a median of 7 prior systemic therapies and 81% of patients had ≥2 metastatic sites. In the combination cohort, patients began enrolling in September 2013 with the last patient enrolled in January 2014. Patients in the combination cohort had a median of 4 prior systemic therapies and 67% of patients had ≥2 metastatic sites. An updated analysis will be presented for objective response rate, duration of treatment and clinical benefit rate and will include an additional 6 months of information for both the single-agent and combination cohorts. New analyses will include time to response, duration of response, change in tumor size over time, and characteristics of responders. In addition, safety data will include longer term follow-up through approximately September 2014. Conclusions: Abemaciclib is an oral cell cycle inhibitor that demonstrates single-agent activity against mBC, especially for HR+ disease. Based on its safety and efficacy profile, abemaciclib warrants further clinical investigation in confirmatory studies, both as a single agent and in combination with endocrine therapy. Citation Format: Sara M Tolaney, Lee S Rosen, Muralidhar Beeram, Jonathan W Goldman, Leena Gandhi, Anthony W Tolcher, Kyriakos P Papadopoulos, Drew W Rasco, Scott P Myrand, Palaniappan Kulanthaivel, Joan M Andrews, Martin Frenzel, Damien M Cronier, Edward M Chan, Keith T Flaherty, Patrick Y Wen, Geoffrey I Shapiro, Amita Patnaik. Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic 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 P5-19-13.