On December 5, 2018 ADC Therapeutics, an oncology drug discovery and development company that specializes in the development of proprietary antibody drug conjugates (ADCs), reported that updated data from ongoing Phase I clinical trials of ADCT-402 (loncastuximab tesirine) and ADCT-301 (camidanlumab tesirine) in multiple subtypes of lymphoma during oral and poster presentations at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego (Press release, ADC Therapeutics, DEC 5, 2018, View Source [SID1234596070]).

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"We are encouraged by the safety profiles and strong single-agent anti-tumor activity we continue to observe in the 183-patient first-in-human clinical trial of ADCT-402 and the 113-patient trial of ADCT-301," said Jay Feingold, MD, PhD, Chief Medical Officer and Senior Vice President of Clinical Development at ADC Therapeutics. "The updated ADCT-402 data presented at ASH (Free ASH Whitepaper) support its continued evaluation in our ongoing pivotal clinical trial in patients with relapsed or refractory diffuse large B-cell lymphoma. For ADCT-301, we now have the dosing data to support further investigation in a planned pivotal Phase II trial in patients with relapsed or refractory Hodgkin lymphoma, which we look forward to initiating in 2019."

ADCT-402 Oral and Poster Presentations at ASH (Free ASH Whitepaper)

Interim Results from the First-in-Human Clinical Trial of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (Abstract 398)

Oral presentation: John Radford, MD, FRCP, Manchester Academic Health Centre, The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK

Data were presented from a subpopulation of 139 evaluable patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who had failed or were intolerant to established therapies. The patients had a median age of 63 years and had received a median of three previous therapies. Patients received doses of ADCT-402 ranging from 15 to 200 μg/kg every three weeks. The median number of cycles received was two and the median duration of treatment was 43 days.

Key findings from the oral presentation include:

ADCT-402 has demonstrated manageable toxicity in patients with R/R DLBCL
At doses >120 μg/kg, the overall response rate (ORR) was 43.3% (55/127 patients with DLBCL), comprising 23.6% complete responses and 19.7% partial responses
At doses >120 μg/kg, after a median follow up of 5.5 months, median duration of response (DoR) was not reached in patients achieving a complete response
A pivotal Phase II study is currently enrolling patients with R/R DLBCL to evaluate the efficacy and safety of ADCT-402 at dose 150 μg/kg every three weeks for two cycles followed by dose 75 μg/kg every three weeks (NCT03589469).

Safety and Efficacy of ADCT-402 (Loncastuximab Tesirine), a Novel Antibody Drug Conjugate, in Relapsed/Refractory Follicular Lymphoma and Mantle Cell Lymphoma: Interim Results from the Phase I First-in-Human Study (Abstract 2874)

Poster presentation: Paolo Caimi, MD, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH

Data were presented from a subgroup of 29 patients, including 14 patients with follicular lymphoma (FL) and 15 patients with mantle cell lymphoma (MCL). The median age of the FL patients was 60.5 years and the median age of the MCL patients was 64 years. Patients received infusions every three weeks at doses ranging from 15 to 200 μg/kg. Patients with FL and MCL received a median of three and two cycles of ADCT-402, respectively.

Key findings from the poster presentation include:

ADCT-402 has demonstrated manageable toxicity in patients with R/R FL and R/R MCL
In patients with FL, ORR was 78.6% (11/14) and median DoR was not reached after a median follow-up time of 11.6 months
In patients with MCL, ORR was 46.7% (7/15) and median DoR was not reached after a median follow-up time of 8.7 months
ADCT-301 Oral and Poster Presentations at ASH (Free ASH Whitepaper)

Phase I Study of ADCT-301 (Camidanlumab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Classical Hodgkin Lymphoma (Abstract 928)

Oral presentation: Mehdi Hamadani, MD, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI

Data were presented from 67 evaluable, heavily pretreated patients with relapsed/refractory (R/R) classical Hodgkin Lymphoma (HL) who had failed or were intolerant to any established therapy known to provide clinical benefit. The median age of the patients was 38 years and they had received a median of five prior therapies. Patients were treated with doses of ADCT-301 ranging from 5 to 300 μg/kg. They completed a median of three cycles of treatment and median treatment duration was 43 days.

Key findings from the oral presentation include:

ADCT-301 has demonstrated manageable toxicity in patients with R/R HL
The most common Grade 3 or 4 treatment-emergent adverse events occurring in at least 5 percent of patients, regardless of attribution, at the 45 μg/kg dose in 37 patients were: maculopapular rash (18.9 percent),elevated gamma-glutamyltransferase (8.1 percent), elevated alanine aminotransferase (8.1 percent), elevated aspartate aminotransferase (2.7 percent), anemia (8.1 percent), Guillain-Barré syndrome / radiculopathy (8.1 percent) and increased lipase (8.1 percent)
In patients with R/R HL, therapy with ADCT-301 achieved an overall response rate (ORR) of 86.5% and a complete response rate of 43% in the 37 patients in the 45 μg/kg dose group who had received and failed prior brentuximab vedotin and most of whom had failed prior checkpoint inhibitor treatment
These data support further investigation of the 45 μg/kg dose of ADCT-301 in a planned pivotal Phase II study anticipated to commence in 2019
ADCT-301 (Camidanlumab Tesirine), a Novel Pyrrolobenzodiazepine-Based CD25-Targeting Antibody Drug Conjugate, in a Phase I Study of Relapsed/Refractory Non-Hodgkin Lymphoma Shows Activity in T-Cell Lymphoma (Abstract 1658)

Poster presentation: Graham P. Collins, MB, BS, DPhil, Oxford University Hospitals, NHS Trust, Oxford, UK

Data were presented from 44 patients with R/R non-Hodgkin lymphoma (NHL) with a median age of 65.5 years who had received a median number of four previous systemic therapies (including prior stem cell transplant). Of those, 22 patients were in a T-cell lymphoma subgroup. Patients were treated with doses of ADCT-301 ranging from 3 to 150 μg/kg and received a median number of two cycles. Median treatment duration was 22 days.

Key findings from the poster presentation include:

ADCT-301 demonstrated an acceptable safety profile during dose-escalation
Overall, in patients with R/R NHL, therapy with ADCT-301 achieved an ORR of 31.7% (13/41) at doses >60 μg/kg
In the R/R T-cell lymphoma subgroup, therapy with ADCT-301 achieved an ORR of 53.8% (7/13) in the 60 and 80 μg/kg dose groups
These data support further investigation of ADCT-301 in T-cell lymphoma
About ADCT-402

ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) composed of a humanized monoclonal antibody that binds to human CD19, conjugated through a linker to a pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD19-expressing cell, ADCT-402 is internalized into the cell where enzymes release the PBD-based warhead. CD19 is a clinically validated target for the treatment of B-cell malignancies. The PBD-based warhead has the ability to form highly cytotoxic DNA interstrand cross-links, blocking cell division and resulting in cell death. ADCT-402 is being evaluated in a pivotal Phase II clinical trial in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (NCT03589469). The U.S. Food and Drug Administration granted orphan drug designation to ADCT-402 for the treatment of DLBCL and mantle cell lymphoma.

About ADCT-301

ADCT-301 (camidanlumab tesirine) is an antibody drug conjugate (ADC) composed of a monoclonal antibody that binds to CD25 (HuMax-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload tesirine. Once bound to a CD25-expressing cell, ADCT-301 is internalized into the cell where enzymes release the PBD-based warhead. The intra-tumor release of its PBD warhead may cause bystander killing of neighboring tumor cells. In addition, the PBD warhead will trigger immunogenic cell death, which in turn will strengthen the immune response against tumor cells. ADCT-301 is being evaluated in ongoing Phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma (NCT02432235), as well as a Phase Ib clinical trial in solid tumors (NCT03621982).

On December 5, 2018 Apexian Pharmaceuticals reported that Chemotherapy causes chemotherapy-induced peripheral neuropathy (CIPN) in a significant number of patients, yet the pharmaceutical landscape is completely devoid of treatments to prevent CIPN (Press release, Apexian Pharmaceuticals, DEC 5, 2018, View Source [SID1234532133]). The tingling, burning, pain or numbness in the extremities can limit or stop cancer treatment. And, in half the patients affected, CIPN’s symptoms persist five years or more after treatment ends. Apexian Pharmaceuticals aims to change that with their lead compound, APX3330.

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Data presented at the meeting showed continued preclinical support for APX3330 as a potential anti-CIPN treatment, particularly for patients treated with cisplatin or oxaliplatin. Preclinical results presented show APX3330 can block tumor growth while protecting nerve cells.

APX3330, an oral treatment, is currently in a Phase I oncology trial for safety. A Phase II trial is planned in 2019 for anti-tumor and anti-CIPN.

Apexian’s founder and Chief Science Officer, Mark Kelley, PhD, presented the trial’s results in ASCO (Free ASCO Whitepaper)’s Symptom Management Meeting in San Diego, November 16-18, 2018.

Currently ASCO (Free ASCO Whitepaper) does not recommend any drug for preventing or treating CIPN.

"CIPN is a disease with high unmet need and it is exciting to see that APX3330 may have a role to play in addressing the need", says Steve Carchedi, President & CEO of Apexian. "We are committed to developing a portfolio of novel APE1/Ref-1 compound’s that will enhance the lives of patients."

The success of APX3330 builds upon three decades of research by Kelley and his colleagues in modulating a key DNA repair protein, APE1/Ref-1. APX3330 tweaks the protein’s activity to prevent or repair neuronal damage without stimulating cancerous tumors.

APX3330 is Apexian’s lead compound in its growing drug development pipeline.

On December 5, 2018 iCell Gene Therapeutics, LLC reported results from a study ongoing at Chengdu Military General Hospital of ICG144, the first CLL1-CD33 Compound CAR T-cell (cCAR) in clinical study, in patients with particularly difficult to treat Acute Myeloid Leukemia (AML) (Press release, iCell Gene Therapeutics, DEC 5, 2018, View Source [SID1234531930]). Patients 1 and 2 both failed multiple previous cycles of therapy and presented with complex conditions limiting further options. Treatment with CLL1-CD33 cCAR led both patients to complete response and engraftment of haploidentical stem cell transplantation (allo-HSCT) without myeloablative conditioning.

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"Patient response seen to date is encouraging for refractory AML patients, and opens the potential of this novel therapy as bridge to transplant, a supplement to chemotherapy, or as a standalone therapy for patients with acute myeloid leukemia." stated Dr. Fang Liu, MD, PhD, the Principal Investigator of the study who presented the results at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego. Dr. Yupo Ma, MD, PhD, Chairman of iCell Gene Therapeutics added, "Initial patient experience highlights the potential importance of iCell’s proprietary multiple antigen targeting and enhancing technologies to overcome antigen escape and improve treatment outcomes."

Upon enrollment, patients receive a lymphodepletion regimen consisting of fludarabine and cyclophasphamide followed by 1×106 – 2×106 CAR T cells/kg, nonmyeloablative conditioning and Haplo-HSCT

Patient 1 is a 6-year-old originally diagnosed with Franconi anemia transformed JMML and eventually to AML-M5 with more than 90% blasts in the marrow, complex karyotype and FLT3-ITD mutation.
Patient 2 is a 23-year-old, failed to TKIs, AP-CML (basophils>20%, plt>1000X109/L), T315I mutation.
Complete response and Haplo-HSCT engraftment was observed in both patients.
Grade 1 CRS and pancytopenia was observed in both patients.
Grade 3 neurotoxicity was observed in Patient 1.
About CLL1-CD33 cCAR T cell therapy

CLL1-CD33 cCAR is a compound Chimeric Antigen Receptor (cCAR) immunotherapy with two distinct functional CAR molecules expressed on a T-cell, directed against the surface proteins CLL1 and CD33. The diseases treated by CLL1-CD33 cCAR could include acute myeloid leukemia, myelodysplastic syndromes, chronic myeloid leukemia and chronic myeloproliferative neoplasms. CLL1 is associated with leukemia stem cells and disease relapse, while CD33 is expressed on bulky AML disease. Treatment of AML is a challenge due to heterogeneity of AML bearing cells, which renders single antigen targeting CAR T-cell therapy ineffective. ICG144 cCAR is designed to target the mechanisms of single-CAR relapse, specifically antigen escape and leukemic stem cells.

About AML

Acute myeloid leukemia (AML) is the abnormal proliferation of immature myeloid cells and the most common leukemia in adults. Prognosis is dismal when AML relapses or is refractory to chemotherapy. Mortality associated with this disease is high, with approximately 10,000 deaths in 2018 in the US.

On December 5, 2018 Protagonist Therapeutics, Inc. (NASDAQ:PTGX) reported that Dinesh V. Patel, Ph.D., President and Chief Executive Officer, will provide a corporate overview at the BMO Capital Markets 2018 Prescriptions for Success Healthcare Conference in New York (Press release, Protagonist, DEC 5, 2018, View Source;p=RssLanding&cat=news&id=2379597 [SID1234531922]).

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Presentation details:

Event:

BMO Capital Markets 2018 Prescriptions for Success Healthcare Conference

Date:

Wednesday, Dec. 12, 2018

Time:

9:20 a.m. EST

A live and archived audio webcast of the presentation can be accessed by visiting the Investors page of the Protagonist Therapeutics website at View Source

On December 5, 2018 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that updated efficacy and safety results from the ongoing phase 1/2 study of U3-1402, an investigational and potential first-in-class HER3-targeting antibody drug conjugate (ADC), in 42 heavily pretreated patients with HER3-positive metastatic breast cancer were presented during a Spotlight Session at the 2018 San Antonio Breast Cancer Symposium (SABCS) (Press release, Daiichi Sankyo, DEC 5, 2018, View Source [SID1234531918]).

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Updated efficacy data for 42 evaluable patients who received U3-1402 in dose levels between 1.6 mg/kg to 8.0 mg/kg in the dose escalation and dose finding parts of the study showed a confirmed overall response rate of 42.9 percent (18/42 patients) and a disease control rate of 90.5 percent (38/42 patients) at a median follow-up time of 10.5 months. A median duration of response was not reached (range: 2.8, 13.8+). The median progression-free survival was 8.3 months (range: 1.2, 16.8+). Efficacy was observed in all molecular subtypes. A total of 21 patients remain on treatment at the time of data cut-off on November 6, 2018.

"These results offer preliminary evidence of U3-1402 activity in HER3-positive metastatic breast cancer and further study is warranted," said Norikazu Masuda, MD, PhD, National Hospital Organization, Osaka National Hospital, Osaka, Japan, and an investigator for the trial. "The initial efficacy and safety data suggest that a HER3-targeting agent such as U3-1402 could provide a new treatment approach for patients with HER3-expressing metastatic breast cancer, who are in need of additional options to manage their disease."

Updated safety results were also reported. With a median exposure to treatment of 7.6 months, U3-1402 showed a manageable safety profile. The most common adverse events (≥30 percent, any grade) included nausea (85.7 percent), thrombocytopenia (71.4 percent), decreased appetite (66.7 percent), neutropenia (64.3 percent), leukopenia (59.5 percent), vomiting (54.8 percent), AST increased (47.6 percent), ALT increased (45.2 percent), anemia (38.1 percent), stomatitis (35.7 percent) and diarrhea (31.0 percent). The most common adverse events Grade ≥3 (>10 percent of patients) were thrombocytopenia (35.7 percent), neutropenia (28.6 percent), leukopenia (21.4 percent), anemia (16.7 percent) and ALT increased (11.9 percent). Fourteen (14) patients (33.3 percent) experienced serious adverse events regardless of causality, and seven (7) patients (16.7 percent) experienced serious adverse events that were treatment-related. One (1) patient experienced an adverse event leading to treatment discontinuation (2.4 percent), and there were no adverse events leading to death.

"We are encouraged by these preliminary findings with U3-1402, particularly because there are no therapies specifically approved for HER3-expressing breast cancer," said Kouichi Akahane, PhD, MBA, Executive Officer, Head of Oncology Function, R&D Division, Daiichi Sankyo. "Additionally, these findings continue to build evidence that supports the portability of Daiichi Sankyo’s proprietary DXd and linker ADC technology to other targets such as HER3."

About the Phase 1 Study

In this three-part open-label global phase 1/2 study, U3-1402 is given as an intravenous infusion every three weeks. The first part of the study (dose escalation) assessed the safety, tolerability and maximum tolerated dose of U3-1402 in HER3-positive (defined as IHC [immunohistochemistry] 2+/3+) metastatic breast cancer patients who are refractory or intolerant to standard treatment or for whom no standard treatment is available. A maximum tolerated dose has not been reached. Based on preliminary results, dose levels of 4.8 mg/kg and 6.4 mg/kg are being further evaluated. The second part of the study (dose finding) is assessing the safety and efficacy of U3-1402 and determining the recommended phase 2 dose in HER3-positive metastatic breast cancer patients who have received six or fewer prior chemotherapy regimens. The third part of the study (phase 2) is assessing the safety and efficacy of the recommended dose of U3-1402 in HER3-positive metastatic breast cancer patients who have received six or fewer prior chemotherapy regimens. The study is currently enrolling patients in Japan and the U.S. For more information about this study, please visit ClinicalTrials.gov.

About HER3-Positive Metastatic Breast Cancer

HER3 is a member of the human epidermal growth factor receptor family of tyrosine kinase receptors, which are associated with aberrant cell growth.¹ HER3 is overexpressed in several types of solid tumors including breast cancer.² HER3 overexpression has been independently associated with a poorer prognosis and reduced survival for patients with invasive breast cancer.¹ A wide range of incidence of HER3 overexpression has been reported in breast cancer, depending on the screening method and published series.¹ There are currently no targeted therapies approved specifically for HER3-expressing breast cancer or any HER3-expressing cancer.

About U3-1402

Part of the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise, U3-1402 is an investigational and potential first-in-class HER3-targeting ADC. ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy ("payload") to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, U3-1402 is comprised of a human anti-HER3 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

U3-1402 is currently being evaluated in two clinical studies, including the phase 1/2 study for HER3-expressing metastatic or unresectable breast cancer in Japan and the U.S., and a phase 1 study for metastatic or unresectable EGFR-mutated non-small cell lung cancer (NSCLC) in the U.S.

U3-1402 is an investigational agent that has not been approved for any indication in any country. Safety and efficacy have not been established.