Zybrestat (fosbretabulin) / Oncotelic - LARVOL DELTA

Nanomedicine mediated thyroid cancer diagnosis and treatment: an approach from generalized to personalized medicine. (PubMed, Discov Oncol) - "Chemotherapy includes the use of doxorubicin or taxanes generally with platinum-based drugs viz. cisplatin or carboplatin that are administered alone or along with multitarget tyrosine kinase inhibitors viz. Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Pyrazolo-pyrimidine compounds, etc., single target tyrosine kinase inhibitors like Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, Everolimus against mTOR, vascular disruptors like Fosbretabulin, and immunotherapy with viz. Spartalizumab and Pembrolizumab, are anti-PD-1/PD-L1 molecules...Hence, our review presents a closer view of NDDS as a personalized treatment for TC. We have also discussed the primary challenges facing NDDS in meeting excellence in PM."

IO biomarker • Journal • Review • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • EGFR

Impact of Blood-Brain Barrier to Delivering a Vascular-Disrupting Agent: Predictive Role of Multiparametric MRI in Rodent Craniofacial Metastasis Models. (PubMed, Cancers (Basel)) - "Postmortem angiography and pathology showed a significantly larger H&E-stained area of necrosis (86.2% vs. 18.3%, p < 0.0001), lower CD31 level (42.7% vs. 54.3%, p < 0.05), and lower Ki67 level (12.2% vs. 32.3%, p < 0.01) in extracranial tumors, compared with intracranial lesions. The BBB functioned as a barrier against the delivery of VDA into intracranial tumors and multiparametric MRI may predict the efficacy of VDAs on craniofacial tumors."

Journal • Preclinical • Immunology • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • CD31 • PECAM1

A phase II study of combretastatin A4-phosphate (CA4P) in the treatment of well-differentiated, low- to intermediate-grade, unresectable, recurrent, or metastatic pancreatic, or GI neuroendocrine tumors/carcinoid (GI-NETs/PNETs) with elevated biomarkers. (ASCO-GI 2017) - P2; "The primary endpoint was not met. However, the number of pts entering the rollover study and ORR suggest that CA4P conferred some activity and was generally safe and well tolerated. These findings suggest that due to their inherent variability, tumor biomarkers may not be an ideal endpoint for this population."

P2 data • Biliary Cancer • Biosimilar • Cardiovascular • Gastrointestinal Cancer • Oncology • Pain • Reperfusion Injury

The Efficacy of Fosbretabulin Disodium Combined with Radiofrequency Ablation in Lung Cancer. (PubMed, Radiat Res) - "Mechanistically, we reported that FBTD inhibited the RFA-induced PD-1 and PD-L1 upregulation in vivo. In conclusion, we demonstrated that FBTD promoted the antitumor effects of RFA in lung tumor-bearing mice in this study."

IO biomarker • Journal • Lung Cancer • Oncology • Solid Tumor • CD8 • IFNG • TNFA

Advances in targeted therapy for anaplastic thyroid carcinoma. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "Tyrosine kinase inhibitor lenvatinib has potential in treating ATC patients with favorable efficacy in clinical trials. The effectiveness of the v-raf murine sarcoma viral oncogene homologue B1 () gene inhibitor dabrafenib in combination with trametinib for the treatment of positive ATC patients has been demonstrated in clinical trials...The immune checkpoint inhibitor pembrolizumab can be applied to treat thyroid cancer with high tumor mutational load and may be considered as the preferred modality for the treatment of ATC patients with high programmed death ligand-1 expression. The mammalian target of rapamycin pathway inhibitors, peroxisome proliferators-activated receptor γ agonists, endothelial growth factor receptors-targeting monoclonal antibody cetuximab and novel vascular blocker fosbretabulin are still in the clinical research stage, which are expected to provide new directions for the development of novel targeted drugs. This article reviews the current..."

IO biomarker • Journal • Endocrine Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • PD-L1 • TMB

Oncotelic Initiates Phase 1 Trial Evaluating CA4P in Combination with Pembrolizumab for Melanoma (GlobeNewswire) - "Oncotelic Therapeutics...announced that it has submitted a clinical study protocol to the United States Food and Drug Administration ('US FDA') for the initiation of a Phase 1 Clinical Trial for CA4P, the Company’s Vascular Disrupting Agent, in combination with Anti-PD-1 (pembrolizumab) as a treatment for patients with Melanoma. The Phase 1 Clinical Trial is designated as S101: Phase 1, Prospective, Multicenter, Open-Label, Single Arm Study of Safety and Initial Efficacy of CA4P in Combination with anti-PD1 (pembrolizumab) in Patients with Recurrent Metastatic Cutaneous or Uveal Melanoma."

IND • New P1 trial • Cutaneous Melanoma • Melanoma • Oncology • Skin Cancer • Solid Tumor • Uveal Melanoma

Imidazole Analogs of Vascular-Disrupting Combretastatin A-4 with Pleiotropic Efficacy against Resistant Colorectal Cancer Models. (PubMed, Int J Mol Sci) - "The bromo derivative brimamin was then compared with the known fosbretabulin (CA-4P) by activity tests on DLD-1- (multidrug-resistant) and HT29- (CA-4-resistant) derived xenograft tumors...In conclusion, combretastatin analogous N-methylimidazoles proved capable of inducing vascular-disrupting effects, comparable to those of CA-4P. In addition, they showed antitumor activities in models of drug-resistant colorectal cancer, independent of vascular-disrupting effects."

Clinical • Journal • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors. (ASCO 2019) - "Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429."

Clinical • Combination therapy • P1 data • Neuroendocrine Tumor • Oncology • Solid Tumor

A Phase Ib and Randomised Phase II Trial of Pazopanib with or without Fosbretabulin in Advanced Recurrent Ovarian Cancer (ESMO 2018) - "Any Bevacizumab had been received ≥6 months prior to recruitment. F54+P600 appeared effective but was associated with reversible secondary cardiac toxicity that with better hypertension control might have been avoided."

Clinical • P2 data • Ovarian Cancer

A phase I/II study of fosbretabulin in combination with everolimus in neuroendocrine tumors that have progressed after at least one prior regimen for metastatic disease. (ASCO 2018) - P1; "Patients will be treated with daily oral everolimus. Fosbretabulin will be administered IV either q3 weekly or q weekly based on partial order continuous reassessment model (PO CRM)."

Combination therapy • P1/2 data • Gastrointestinal Cancer • Neuroendocrine Tumor • Ovarian Cancer

A Phase I study of Fosbretabulin in combination with everolimus in neuroendocrine tumors (Grades 1-3) that have progressed after at least one prior regimen for metastatic disease (AACR 2019) - "Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. ClinicalTrials.gov Identifier: NCT0301429"

Combination therapy • P1 data • Gastrointestinal Cancer • Gynecologic Cancers • Neuroendocrine Tumor • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor

Recent advances in the management of anaplastic thyroid cancer. (PubMed, Thyroid Res) - "Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin)...These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules)...Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression,..."

IO biomarker • Journal • Review • Immune Modulation • Inflammation • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF • EGFR

Hypothyroidism to predict for long term survival in patients with fosbretabulin treated anaplastic thyroid carcinoma. (ASCO 2018) - "...Further treatment included palliative radiation, efatutazone plus paclitaxel, lenvatinib and pembrolizumab...TSH levels were noted to be elevated despite increasing levels of levothyroxine replacement... This represents the second long-term survivor with unresectable ATC treated with fosbretabulin. A randomized phase II trial of fosbretabulin plus paclitaxel and carboplatin versus carboplatin and paclitaxel alone, failed to meet its endpoint of improved overall survival[i]. However a previously reported patient, aged 55 at diagnosis, survived for 10 years after treatment with combretastatin for locally advanced disease[ii]."

Clinical • PD(L)-1 Biomarker • Thyroid Cancer

Bevacizumab plus fosbretabulin in recurrent ovarian cancer: Overall survival and exploratory analyses of a randomized phase II NRG oncology/gynecologic oncology group study. (PubMed, Gynecol Oncol) - "Although no significant survival benefit was observed, the trend showing a reduced HR for progression or death with increasing tumor size when fosbretabulin is added to bevacizumab compared to bevacizumab alone warrants further study."

Clinical • Journal • P2 data • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. (PubMed, Gynecol Oncol) - "It remains unclear whether pazopanib with with fosbretabulin is an efficacious regimen to treat epithelial ovarian cancer. Effective cardiac risk mitigation is needed to increase the tolerability and maximize patient safety in future trials."

Clinical • Journal • P1 data • P2 data • Fatigue • Gynecologic Cancers • Hematological Disorders • Hypertension • Neutropenia • Oncology • Ovarian Cancer

Mateon: Ladenburg Thalmann Annual Healthcare Conference (Ladenburg Thalman Healthcare Conference 2016, Mateon Therapeutics) - Anticipated initial interim analysis of P2/3 FOCUS trial (NCT02641639) of bevacizumab + CA4P in platinum-resistant ovarian cancer in Q1 2017; Anticipated second interim analysis of P2/3 FOCUS trial in platinum-resistant ovarian cancer in Q2 2017; Anticipated third and fourth interim analyses of P2/3 FOCUS trial in platinum-resistant ovarian cancer in H2 2017; Anticipated transition to part 2 of P2/3 FOCUS trial in platinum-resistant ovarian cancer in H2 2017

Anticipated P2/3 data • Trial status • Biosimilar • Ovarian Cancer

Mateon: Ladenburg Thalmann Annual Healthcare Conference (Ladenburg Thalman Healthcare Conference 2016, Mateon Therapeutics) - Anticipated initial interim analysis of P2/3 FOCUS trial (NCT02641639) of bevacizumab + CA4P in platinum-resistant ovarian cancer in Q1 2017; Anticipated second interim analysis of P2/3 FOCUS trial in platinum-resistant ovarian cancer in Q2 2017; Anticipated third and fourth interim analyses of P2/3 FOCUS trial in platinum-resistant ovarian cancer in H2 2017; Anticipated transition to part 2 of P2/3 FOCUS trial in platinum-resistant ovarian cancer in H2 2017

Anticipated P2/3 data • Trial status • Biosimilar • Ovarian Cancer

Mateon: Ladenburg Thalmann Annual Healthcare Conference (Mateon Therapeutics, Ladenburg Thalman Healthcare Conference 2016) - "Recurrent OC (GOG-01861): Clinical Summary"; "CA4P Bev"; Progression-free Survival (ITT)"; "Progression-free Survival (Platinum Resistant) "

P2 data • Biosimilar • Ovarian Cancer

Mateon: Ladenburg Thalmann Annual Healthcare Conference (Mateon Therapeutics, Ladenburg Thalman Healthcare Conference 2016) - "Recurrent OC (GOG-01861): Clinical Summary"; "CA4P Bev"; Progression-free Survival (ITT)"; "Progression-free Survival (Platinum Resistant) "

P2 data • Biosimilar • Ovarian Cancer

Addition of CA4P to bevacizumab confers modest PFS benefit in platinum-resistant ovarian cancer (Healio) - P2/3, N=40; FOCUS (NCT02641639); Sponsor: Mateon Therapeutics; "Researchers reported a small PFS benefit with the fosbretabulin regimen (median, 6.64 months vs. 4.96 months; HR = 0.68); however, the difference did not reach statistical significance....Four patients (25%) treated with fosbretabulin and six patients (40%) in the control group achieved partial responses. Nine patients (56.3%) treated with fosbretabulin and 11 patients (57.9%) in the control group achieved stable disease."

P2/3 data • Biosimilar • Oncology • Ovarian Cancer

Oxigene announces positive topline results from randomized phase 2 study GOG186I of zybrestat in combination with Avastin for recurrent ovarian cancer (Oxigene Press Release) - P2, N=107; GOG protocol 186I (NCT01305213); "OXiGENE...announced positive results from a randomized Phase 2 clinical trial evaluating Avastin® (bevacizumab) with or without ZYBRESTAT® (fosbretabulin; CA4P) to treat patients with recurrent ovarian cancer. The study, known as Gynecologic Oncology Group protocol 186I, met its primary endpoint of a statistically significant increase in progression-free survival (p-value less than 0.05; hazard ratio 0.685) for the combination as compared to bevacizumab alone."

P2 data • Biosimilar • Oncology • Ovarian Cancer

OXiGENE reports final data from phase 2 FALCON study of ZYBRESTAT in non-small cell lung cancer (Globenewswire) - P2, N=60; FALCON; Median OS was 13.6 months in the ZYBRESTAT arm vs 16.2 months in the standard therapy arm; Median OS in pts with aggregate tumor burden greater than 10 cm was 14.2 months in the ZYBRESTAT arm vs 11.0 months in the standard therapy arm; Median OS in patients with aggregate tumor burden of 10 cm or less was 13.6 months in the ZYBRESTAT arm vs 16.7 months in the standard therapy arm; The addition of ZYBRESTAT to standard therapy appeared to be well tolerated; No significant overlapping toxicities with bevacizumab were observed; Hypertension was increased in pts in the ZYBRESTAT arm of the study but was transient and manageable without significant cardiac toxicity; Median PFS was 8.6 months in the ZYBRESTAT arm vs 9.3 months in the standard therapy arm

P2 data • Non Small Cell Lung Cancer • Oncology

Zybrestat: Second, third and fourth interim analyses of P2/3 FOCUS trial (NCT02641639) of bevacizumab + CA4P in platinum-resistant ovarian cancer in H2 2017 (Mateon Therapeutics) - Corporate Presentation

P2/3 data • Biosimilar • Oncology • Ovarian Cancer

OXiGENE announces restructuring to focus resources on promising earlier stage clinical programs (Globenewswire) - OXiGENE plans to continue its randomized Phase 2 trial of ZYBRESTAT in combination with bevacizumab in patients with relapsed ovarian cancer; OXiGENE is concluding its P2 ZYBRESTAT trial in NSCLC (FALCON study) and any future development decisions concerning the study of ZYBRESTAT in patients with NSCLC will be made following review of final data by OXiGENE's management and its board of directors

Clinical trial update • Non Small Cell Lung Cancer • Oncology

Mateon Therapeutics announces termination of FOCUS study in ovarian cancer and restructuring to prioritize OXi4503 for AML (GlobeNewswire) - P2/3, N=436; NCT02641639; "Mateon Therapeutics...today announced results from its third scheduled interim analysis of the phase 2/3 FOCUS study evaluating CA4P in combination with bevacizumab (Avastin®)...in patients with platinum-resistant ovarian cancer...Due to the lack of a meaningful improvement in PFS, combined with the unfavorable partial response data, the company does not believe that continuation of the study is appropriate."

P2/3 data • Trial suspension • Oncology • Ovarian Cancer