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Cancer Medicine Feb 2020Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet-derived growth factor receptor alpha and blocks ligand binding. This study assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Olaratumab, a fully human monoclonal antibody, selectively binds to human platelet-derived growth factor receptor alpha and blocks ligand binding. This study assessed the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin and the safety of olaratumab alone and in combination with doxorubicin.
METHODS
This open-label randomized phase 1 trial enrolled 49 patients ages 27 to 83 with metastatic or locally advanced soft tissue sarcoma (STS). Patients participated in 21-day treatment cycles (up to 8) until they met discontinuation criteria. In cycles 1 and 2, patients received olaratumab (15 mg/kg in Part A, 20 mg/kg in Part B) and doxorubicin (75 mg/m ). In cycles 3 through 8, patients continued combination treatment (15 mg/kg olaratumab + doxorubicin). Effect of olaratumab on PK of doxorubicin was determined in patients who received all doses in cycles 1 and 2.
RESULTS
PK properties of doxorubicin administered alone or in combination with olaratumab (15 or 20 mg/kg) were similar for AUC(0-t ), AUC(0-∞), and C . PK properties of olaratumab (15 or 20 mg/kg) were also similar when administered alone or in combination with doxorubicin. Three patients died (2 of disease progression and 1 of neutropenic enterocolitis). Fatigue and nausea (>75% of patients) were the most common treatment-emergent adverse events (TEAEs). Other common TEAEs included musculoskeletal pain, mucositis, constipation, and diarrhea.
CONCLUSIONS
Olaratumab at 15 or 20 mg/kg before doxorubicin infusion had no clinically relevant effect on systemic exposure to doxorubicin compared with doxorubicin alone in patients with metastatic or locally advanced STS.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Doxorubicin; Drug Interactions; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Staging; Sarcoma
PubMed: 31821732
DOI: 10.1002/cam4.2728 -
Cancer Science Jul 2014Olaratumab (IMC-3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet-derived growth factor receptor-α with high...
Olaratumab (IMC-3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet-derived growth factor receptor-α with high affinity and blocks ligand binding. This was a single-center, dose-escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose-limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab-related treatment-emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab-related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab-related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated.
Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Agents; Asian People; Becaplermin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Proteinuria; Proto-Oncogene Proteins c-sis; Treatment Outcome
PubMed: 24816152
DOI: 10.1111/cas.12444 -
BMC Cancer Dec 2018Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a... (Comparative Study)
Comparative Study Randomized Controlled Trial
Randomized phase II study of the PDGFRα antibody olaratumab plus liposomal doxorubicin versus liposomal doxorubicin alone in patients with platinum-refractory or platinum-resistant advanced ovarian cancer.
BACKGROUND
Olaratumab is a platelet-derived growth factor receptor-α (PDGFRα)-targeting monoclonal antibody blocking PDGFRα signaling. PDGFRα expression is associated with a more aggressive phenotype and poor ovarian cancer outcomes. This randomized, open label phase II study evaluated olaratumab plus liposomal doxorubicin compared with liposomal doxorubicin alone in advanced ovarian cancer patients.
METHODS
Patients with platinum-refractory or platinum-resistant advanced ovarian cancer were randomized 1:1 to receive liposomal doxorubicin (40 mg/m, intravenous infusion) administered every 4 weeks with or without olaratumab (20 mg/kg, IV infusion) every 2 weeks. Patients were stratified based on prior response to platinum therapy (refractory vs resistant). The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate, duration of response, and safety.
RESULTS
A total of 123 patients were treated (62 olaratumab+liposomal doxorubicin; 61 liposomal doxorubicin). Median PFS was 4.2 months for olaratumab+liposomal doxorubicin and 4.0 months for liposomal doxorubicin (stratified hazard ratio [HR] = 1.043; 95% confidence interval [CI] 0.698-1.558; p = 0.837). Median OS was 16.6 months and 16.2 months in the olaratumab+liposomal doxorubicin and liposomal doxorubicin arms, respectively (HR = 1.098; 95% CI 0.71-1.71). In the platinum-refractory subgroup, median PFS was 5.5 months (95% CI 1.6-9.2) and 3.7 months (95% CI 1.9-9.2) in the olaratumab+liposomal doxorubicin (n = 15) and liposomal doxorubicin arms (n = 16), respectively (HR = 0.85; 95% CI 0.38-1.91). Overall, 59.7% (olaratumab+liposomal doxorubicin) and 65.6% (liposomal doxorubicin) of patients reported grade ≥ 3 adverse events regardless of causality. The most common treatment-emergent adverse events (all grades) regardless of causality were fatigue related (61%), nausea (57%), and constipation (52%) with olaratumab+liposomal doxorubicin and nausea (64%), fatigue related (62%), and mucositis (46%) with liposomal doxorubicin.
CONCLUSIONS
The addition of olaratumab to liposomal doxorubicin did not result in significant prolongation of PFS or OS in platinum-resistant or platinum-refractory ovarian cancer.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT00913835 ; registered June 2, 2009.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cisplatin; Constipation; Doxorubicin; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Middle Aged; Mucositis; Nausea; Neoplasm Recurrence, Local; Ovarian Neoplasms; Polyethylene Glycols; Progression-Free Survival; Receptor, Platelet-Derived Growth Factor alpha; Time Factors
PubMed: 30591028
DOI: 10.1186/s12885-018-5198-4 -
Chinese Clinical Oncology Aug 2018Soft-tissue sarcoma (STS) is a group of rare but highly heterogeneous neoplasms. Systemic treatment with cytotoxic chemotherapy and targeted agents is one of the main... (Review)
Review
Soft-tissue sarcoma (STS) is a group of rare but highly heterogeneous neoplasms. Systemic treatment with cytotoxic chemotherapy and targeted agents is one of the main therapeutic modalities in patients with unresectable or metastatic disease, while adjuvant and neoadjuvant chemotherapy for adult-type sarcomas remain controversial. Although an anthracycline (doxorubicin) and ifosfamide remain the cornerstone for chemotherapy, advances have been made recently to exceed its limited efficacy, other agents such as trabectedin, eribulin have been approved. In a recent study, the addition of platelet-derived growth factor receptor (PDGFR) antibody-olaratumab to doxorubicin resulted in prolongation of progression-free survival and overall survival, which really means a breakthrough for STS. There is more emerging evidence of different sensitivity to treatment for different histological subtypes, second-line treatment for advanced sarcoma is being increasingly driven by histology. Cytotoxic drugs such as dacarbazine, gemcitabine, and taxanes have shown moderate activity in specific subtypes. Tyrosine kinase inhibitors (TKIs), including pazopanib and anlotinib, appear to be the promising targeted therapies. Other signal pathway inhibitors as CDK4/CDK6 inhibitor, imatinib, mTOR inhibitors, ALK inhibitor has shown some preliminary effect that need to be verified in the future trials. Checkpoint inhibitors as anti-PD-1 and CTLA-4 monoclonal antibodies have been used as a single agent or in combination in the early clinical trials, while further research needs to focus on better patient selection and new combinational strategies. In this review, we aim to summarize the advances of chemotherapy, targeted therapy and immunotherapy in the management of STS.
Topics: Adult; Antineoplastic Agents; Female; Humans; Male; Sarcoma; Young Adult
PubMed: 30173532
DOI: 10.21037/cco.2018.08.02 -
Clinical Pharmacokinetics Mar 2018Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Olaratumab is a recombinant human monoclonal antibody that binds to platelet-derived growth factor receptor-α (PDGFRα). In a randomized phase II study, olaratumab plus doxorubicin met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement in overall survival versus doxorubicin alone in patients with advanced or metastatic soft tissue sarcoma (STS). In this study, we characterize the pharmacokinetics (PKs) of olaratumab in a cancer patient population.
METHODS
Olaratumab was tested at 15 or 20 mg/kg in four phase II studies (in patients with nonsmall cell lung cancer, glioblastoma multiforme, STS, and gastrointestinal stromal tumors) as a single agent or in combination with chemotherapy. PK sampling was performed to measure olaratumab serum levels. PK data were analyzed by nonlinear mixed-effect modeling techniques using NONMEM.
RESULTS
The PKs of olaratumab were best described by a two-compartment PK model with linear clearance (CL). Patient body weight was found to have a significant effect on both CL and central volume of distribution (V ), whereas tumor size significantly affected CL. A small subset of patients developed treatment-emergent anti-drug antibodies (TE-ADAs); however, TE-ADAs did not have any effect on CL or PK time course of olaratumab. There was no difference in the PKs of olaratumab between patients who received olaratumab as a single agent or in combination with chemotherapy.
CONCLUSION
The PKs of olaratumab were best described by a model with linear disposition. Patient body weight and tumor size were found to be significant covariates. The PKs of olaratumab were not affected by immunogenicity or chemotherapeutic agents.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Disease-Free Survival; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Male; Middle Aged; Models, Biological; Neoplasm Metastasis; Neoplasms; Nonlinear Dynamics; Receptor, Platelet-Derived Growth Factor alpha; Survival Rate; Time Factors; Young Adult
PubMed: 28620891
DOI: 10.1007/s40262-017-0562-0 -
Cancers Oct 2023Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there...
Gemcitabine plus docetaxel is an effective treatment regimen for advanced soft tissue sarcomas (STSs). However, the prognosis for patients remains poor, and thus there is an urgent medical need for novel and effective therapies to improve long-term outcomes. The aim of the ANNOUNCE 2 trial was to explore the addition of olaratumab (O) to gemcitabine (G) and docetaxel (D) for advanced STS. Adults with unresectable locally advanced/metastatic STS, ≤2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. In Phase 2, patients were randomized 1:1 from two cohorts (O-naïve and O-pretreated) to 21-day cycles of olaratumab (20 mg/kg Cycle 1 and 15 mg/kg other cycles, Days 1 and 8), gemcitabine (900 mg/m, Days 1 and 8), and docetaxel (75 mg/m, Day 8). The primary objective was overall survival (OS) in the O-naïve population (α level = 0.20). Secondary endpoints included OS (O-pretreated), other efficacy parameters, patient-reported outcomes, safety, pharmacokinetics, and immunogenicity. A total of 167 and 89 patients were enrolled in the O-naïve and O-pretreated cohorts, respectively. Baseline patient characteristics were well balanced. No statistically significant difference in OS was observed between the investigational vs. control arm for either cohort (O-naïve cohort: HR = 0.95 (95% CI: 0.64-1.40), = 0.78, median OS, 16.8 vs. 18.0 months; O-pretreated cohort: HR = 0.67 (95% CI: 0.39-1.16), = 0.15, median OS 19.8 vs. 17.3 months). Safety was manageable across treatment arms. There was no statistically significant difference in the primary endpoint of OS between the two arms in the O-naïve population, and therefore based on hierarchical evaluation no other outcomes in this study can be considered statistically significant. No new safety signals were observed.
PubMed: 37835565
DOI: 10.3390/cancers15194871 -
BMC Cancer Jan 2020The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination...
BACKGROUND
The antibody targeting platelet-derived growth factor receptor alpha (PDGFRA), olaratumab, was approved in 2016 for metastatic soft tissue sarcoma (STS) in combination with doxorubicin based on promising results of a phase Ib/II trial by the Food and Drug Administration (FDA). However, recently the phase III ANNOUNCE trial could not confirm the additional value of olaratumab in this context.
METHODS
Here, in a retrospective analysis we share our single-centre experience with olaratumab/doxorubicin in STS by including n = 32 patients treated with olaratumab/doxorubicin between 2016 and 2019.
RESULTS
Median progression-free survival (PFS) in the overall cohort was 3.1 months (range 0.6-16.2). A response [complete remission (CR), partial remission (PR) or stable disease (SD)] was seen in n = 11 (34%) cases, whereas n = 21 (66%) patients showed progressive disease (PD). In n = 9 patients surgery was performed subsequently in an individual therapeutic approach. Out of n = 5 patients receiving additional regional hyperthermia, n = 3 achieved PR or SD.
CONCLUSIONS
This single-centre experience does also not support the promising phase Ib/II results for olaratumab/doxorubicin in STS. However, our findings do not preclude that olaratumab combination therapy could be valuable in a neoadjuvant setting. This warrants further exploration also taking into account the heterogeneous nature of STS.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Doxorubicin; Female; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Retrospective Studies; Soft Tissue Neoplasms; Treatment Outcome
PubMed: 31996176
DOI: 10.1186/s12885-020-6551-y -
International Journal of Molecular... Mar 2018Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly... (Review)
Review
Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib's approval as a treatment for gastrointestinal stromal tumors (GISTs) has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs) have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor κB ligand (RANKL) inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Bone Neoplasms; Humans; Molecular Targeted Therapy; Sarcoma; Soft Tissue Neoplasms
PubMed: 29510588
DOI: 10.3390/ijms19030739 -
P & T : a Peer-reviewed Journal For... Jan 2017Olaratumab (Lartruvo) for the treatment of soft tissue sarcoma; bezlotoxumab (Zinplava) for use with an antibiotic to reduce recurrence of infection; and doxylamine...
Olaratumab (Lartruvo) for the treatment of soft tissue sarcoma; bezlotoxumab (Zinplava) for use with an antibiotic to reduce recurrence of infection; and doxylamine succinate/pyridoxine hydrochloride (Bonjesta) for the treatment of nausea and vomiting during pregnancy.
PubMed: 28090157
DOI: No ID Found -
MAbs 2017Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend...
Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6-9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US. Brodalumab, was granted a first approval in Japan in July 2016. Regulatory actions on marketing applications for brodalumab in the EU and US are not expected until 2017. In 2017, first EU or US approvals may also be granted for at least nine mAbs (ocrelizumab, avelumab, Xilonix, inotuzumab ozogamicin, dupilumab, sirukumab, sarilumab, guselkumab, romosozumab) that are not yet approved in any country. Based on announcements of company plans for regulatory submissions and the estimated completion dates for late-stage clinical studies, and assuming the study results are positive, marketing applications for at least 6 antibody therapeutics (benralizumab, tildrakizumab, emicizumab, galcanezumab, ibalizumab, PRO-140) that are now being evaluated in late-stage clinical studies may be submitted during December 2016* or 2017. Other 'antibodies to watch' in 2017 include 20 mAbs are undergoing evaluation in pivotal studies that have estimated primary completion dates in late 2016 or during 2017. Of these, 5 mAbs are for cancer (durvalumab, JNJ-56022473, ublituximab, anetumab ravtansine, glembatumumab vedotin) and 15 mAbs are for non-cancer indications (caplacizumab, lanadelumab, roledumab, tralokinumab, risankizumab, SA237, emapalumab, suptavumab, erenumab, eptinezumab, fremanezumab, fasinumab, tanezumab, lampalizumab, brolucizumab). Positive results from these studies may enable submission of marketing applications in 2017 or 2018, or provide justification for additional studies. *See note added in proof for update through December 31, 2016.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Neoplasms; United States
PubMed: 27960628
DOI: 10.1080/19420862.2016.1269580