On June 6, 2016 ProNAi Therapeutics, Inc. (NASDAQ: DNAI), a drug development company advancing targeted therapeutics for patients with cancer, reported interim results from the Wolverine Phase 2 trial of PNT2258 for the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) (Press release, ProNAi Therapeutics, JUN 6, 2016, View Source [SID:1234513054]). ProNAi will host an Analyst and Investor Event today from 7:00-8:00am CT at the Hyatt Regency McCormick Place in Chicago where management will discuss these results and provide an update on the PNT2258 development program.

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"Although we observed modest efficacy from PNT2258 in this interim analysis of Wolverine, we do not view these results as robust enough to justify continued development of the drug in DLBCL. We have decided to suspend development of PNT2258 pending further review of these data in order to determine next steps for both this asset and the DNAi platform," said Dr. Nick Glover, President and CEO of ProNAi. "We continue to maintain a strong balance sheet and will focus our resources and activities on advancing our newly licensed Cdc7 inhibitor, PNT141, as well as on securing additional assets to build a broad and diverse pipeline of oncology drugs under our development."

Wolverine is a multicenter Phase 2 study designed to evaluate the safety and efficacy of PNT2258 monotherapy in 61 response evaluable r/r DLBCL subjects and to explore the correlation between various baseline patient characteristics, including biomarkers, and response rate.

Interim safety and efficacy data as of April 25, 2016 are reported for the first 37 subjects enrolled. PNT2258 showed single-agent activity in r/r DLBCL subjects with a response rate of 8.1% overall (n = 37) and 15.8% in the response evaluable subgroup (n = 19), defined as subjects meeting the amended eligibility criteria of a performance status (PS) of 0-1, exposure to 1-3 prior systemic regimens and having received at least eight doses of PNT2258 within 35 days of starting therapy. No responses were observed in the 10 subjects with a PS of 2 and/or > 4 prior lines of therapy enrolled prior to the amendment, nor to date in the eight additional subjects enrolled subsequent to the data cutoff date for this interim analysis.

PNT2258 is also being evaluated in patients with Richter’s Transformation in the Brighton study, a multi-center, single-arm Phase 2 trial. To date, five subjects have been enrolled in this study, of which four have discontinued. The other subject has completed two cycles of treatment. No responses have been observed to date.

"We designed and conducted a robust, well-executed set of experiments, both clinical and preclinical, in order to further our understanding of the PNT2258 asset and the underlying DNAi technology. Unfortunately, advanced DLBCL and Richter’s Transformation are challenging diseases to treat, and PNT2258 did not markedly improve outcomes in these indications," said Dr. Barbara Klencke, Chief Development Officer of ProNAi. "On the basis of these interim assessments, we have decided to close the Wolverine and Brighton studies to further enrollment of new subjects. On behalf of ProNAi, we would like to thank the patients and their families, investigators and staff involved in these studies for their participation and support."

PNT2258 Development
PNT2258 is a clinical-stage drug candidate based on a new therapeutic approach known as DNA interference (DNAi). The DNAi oligonucleotides contained within PNT2258 are designed to target and hybridize with a complementary strand of genomic DNA associated with the BCL2 oncogene.

PNT2258 was evaluated in two studies prior to the Wolverine Phase 2 trial:

In a Phase 1 study (PNT2258-01 study [NCT01191775]) in 22 subjects with advanced solid tumors, PNT2258 was well tolerated at doses from 1 through 150 mg/m2. A Phase 2 dose and schedule was identified from this study.

A pilot, signal seeking study (PNT2258-02 study [NCT01733238]) conducted at three sites enrolled 13 subjects with r/r B-cell non-Hodgkin’s lymphoma (NHL). Significant, durable responses were observed in the four subjects with DLBCL, along with other noteworthy complete responses (CR) or partial responses (PR) and durable stable disease (SD) in follicular lymphoma subjects. Six subjects were progression free at 12 months and progression free survival extended to two years and beyond in four of these six subjects. The majority of the AEs were Grade 1 or 2 in severity and no Grade 5 AEs were observed. Five of the six subjects who were progression free at 12 months with PNT2258 were relapsed (not refractory) at study entry and had responded with their last prior therapy with a median time-to-treatment failure of 48 months, range 23.7-87.6 months. All four responding DLBCL subjects had received 1 or 2 prior therapies.

Wolverine Phase 2 DLBCL Study Interim Results
The Wolverine Phase 2 trial (PNT2258-03-DLBCL [NCT02226965]) is a multicenter, single-arm, open-label study of PNT2258 at a dose of 120 mg/m2 administered as a 4-hour IV infusion on days 1-5 of a 21-day cycle in adults with r/r FDG-PET positive, measureable DLBCL. Other inclusion criteria included: ECOG PS ≤ 2, adequate bone marrow, renal and hepatic function, and exposure to CD20-targeted therapy, an alkylating agent, and a steroid. Following a protocol amendment, enrollment was limited to patients with PS of 0-1 who had been exposed to 1-3 prior systemic regimens.

The primary objective of the study is to assess overall response rate defined as the proportion of subjects with CR/complete metabolic response (CMR) or PR/partial metabolic response (PMR) according to the revised 2014 International Working Group criteria for lymphoma (Lugano Classification) in approximately 61 response evaluable subjects. Subjects are imaged with FDG-PET/CT at Baseline and after 3, 5, and 8 cycles.

A key study objective is to evaluate biomarker data, including BCL2, MYC, and cell of origin (COO), in order to identify correlations and possible predictors of outcome to treatment with PNT2258. Tumor samples are centrally assessed by IHC for protein expression, FISH for chromosomal rearrangement, and by Lymph2Cx gene expression array for COO.

PNT2258 demonstrated single agent activity in Wolverine, with a response rate of 8.1% overall (n = 37) and 15.8% in the response evaluable subgroup (n = 19); all responses were evaluated as PMR. The disease control rate (disease control rate defined as CMR plus PMR plus no metabolic response) was 18.9% overall and 36.8% in the response evaluable subgroup. Of the 37 subjects, the median progression free survival was 1.9 months.

Overall, the safety profile of PNT2258 appears acceptable in subjects with PS 0-1 and ≤ 3 prior lines of therapy. The median treatment duration was 47 days in these subjects compared with 15.5 days in those with PS of 2 and/or ≥ 4 prior lines of therapy. Serious adverse events (SAE) and Grade 5 adverse events (AE) rates, respectively, were 37% and 11% in the 27 subjects with PS 0-1 and ≤ 3 prior lines of therapy, and 60% and 50% in the 10 subjects with PS 2 and/or ≥ 4 prior lines of therapy.

A full report of this interim analysis, including biomarker data, will be presented at an upcoming medical conference

Brighton Phase 2 Richter’s Transformation Study Update

The Brighton Phase 2 trial (PNT2258-04 Richter’s Transformation [NCT02378038]) is a multicenter, single-arm, open-label study of PNT2258 at a dose of 120 mg/m2 administered as a 4-hour IV infusion on days 1-5 of a 21-day cycle in adults with Richter’s Transformation. To date, five subjects have been enrolled of which four have discontinued. One other subject remains on therapy and has completed two cycles of treatment. No responses have been observed to date.

DNAi Platform Development
ProNAi will also be halting all further investment in the DNAi platform.

Analyst & Investor Event
ProNAi will host an Analyst and Investor Event today, Monday, June 6, 2016 from 7:00 – 8:00am CT where the company will present an update on the PNT2258 development program, including interim results from the Wolverine Phase 2 trial. Presenters will include: Dr. Nick Glover, President and Chief Executive Officer, Dr. Barbara Klencke, Chief Development Officer, Dr. Angie You, Chief Business & Strategy Officer and Head of Commercial, and Dr. Christian Hassig, Senior Vice President, Research. The event will take place in the Hyde Park A/CC11A event room at the Hyatt Regency McCormick Place located at 2233 S. Dr. Martin Luther King Jr. Dr., Chicago, Illinois. This event will be webcast live and will be accessible through the company’s website at www.pronai.com. An archived replay of the webcast will also be available.

ASCO 2016 Poster Presentation
Title: A phase 2 study of PNT2258 in patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL): An initial report from the Wolverine study
Trials in Progress Abstract: #TPS7577
Poster: #130b
Poster Session: Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia
Date and Time: Monday, June 6, 2016, 8:00 – 11:30am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr, Chicago, Illinois
Track: Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia
Presenter: Jason R. Westin, MD, MS, Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center
The poster will be available on June 6, 2016 on the company’s website at www.pronai.com

On June 6, 2016 Nektar Therapeutics (NASDAQ: NKTR) reported new preclinical data for NKTR-214, an immuno-stimulatory CD-122 biased cytokine currently being evaluated in cancer patients with solid tumors in a Phase 1/2 clinical trial being conducted at MD Anderson Cancer Center and Yale Cancer Center (Press release, Nektar Therapeutics, JUN 6, 2016, View Source [SID:1234513074]). The new preclinical data presented demonstrate that treatment with single-agent NKTR-214 mobilizes tumor-killing T cells into colon cancer tumors. In addition, mouse pharmacodynamics data demonstrated that a single dose of NKTR-214 can increase and sustain STAT5 phosphorylation (a marker of IL-2 pathway activation) through one week post-dose. These data were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL from June 3-7, 2016.

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"These latest data build upon our growing body of preclinical evidence demonstrating the unique mechanism of NKTR-214," added Jonathan Zalevsky, PhD, Vice President, Biology and Preclinical Development at Nektar Therapeutics. "The studies presented at ASCO (Free ASCO Whitepaper) show that NKTR-214 promotes tumor-killing immune cell accumulation directly in the tumor, providing a mechanistic basis for its significant anti-tumor activity in multiple preclinical tumor models. The ability to grow TILs1 in vivo and replenish the immune system is exceptionally important. We’ve now learned that many human tumors lack sufficient TIL populations and the addition of the NKTR-214 TIL-enhancing MOA could improve the success of many checkpoint inhibitors and other agents, and allow more patients to benefit from immuno-therapy."

In studies previously published for NKTR-214, when mice bearing established breast cancer tumors are treated with NKTR-214 and anti-CTLA4 (a checkpoint inhibitor therapy known as ipilimumab for human treatment), a large proportion of mice become tumor-free. Anti-tumor immune memory was demonstrated when tumor-free mice were re-challenged by implant with a new breast cancer tumor and then found to clear the new tumor, without further therapy. The new data presented at ASCO (Free ASCO Whitepaper) demonstrate that upon re-challenge, there is a rapid expansion of newly proliferative CD8 T cells and particularly CD8 effector memory T cells. Both cell populations were readily detectable in multiple tissues (blood, spleen, and lymph nodes) and likely contribute to the anti-tumor effect observed in these animals. Adoptive transfer studies confirmed the immune-memory effect as transplant of splenocytes from tumor-free mice into naïve recipients provided the ability to resist tumor growth.

"NKTR-214 provides a highly unique immune activation profile that allows it to access the IL-2 pathway without pushing the immune system into pathological overdrive," said Dr. Steve Doberstein, Senior Vice President and Chief Scientific Officer. "NKTR-214’s unique immune-stimulatory profile and antibody-like dosing schedule positions it as a potentially important medicine within the immuno-oncology landscape."

The data presentation at ASCO (Free ASCO Whitepaper) entitled, "Immune memory in nonclinical models after treatment with NKTR-214, an engineered cytokine biased towards expansion of CD8+ T cells in tumor," can be accessed at View Source

NKTR-214 is a CD122-biased agonist designed to stimulate the patient’s own immune system to kill tumor cells by preferentially activating production of specific immune cells which promote tumor killing, including CD8-positive T cells and Natural Killer (NK) cells, within the tumor micro-environment. CD122, which is also known as the Interleukin-2 receptor beta subunit, is a key signaling receptor that is known to increase proliferation of these types of T cells.2

In preclinical studies, NKTR-214 demonstrated a highly favorable mean ratio of 450:1 within the tumor micro-environment of CD8-positive effector T cells relative to regulatory T cells.3 Furthermore, the pro-drug design of NKTR-214 enables an antibody-like dosing regimen for an immuno-stimulatory cytokine.4

About the NKTR-214 Phase 1/2 Clinical Study
A Phase 1/2 clinical study is underway to evaluate NKTR-214 in patients with advanced solid tumors, including melanoma, renal cell carcinoma and non-small cell lung cancer. The first stage of this study, which is expected to be complete in the second half of 2016, is evaluating escalating doses of single-agent NKTR-214 treatment in approximately 20 patients with solid tumors. The primary objective of the first stage of the study is to evaluate the safety and efficacy of NKTR-214 and to identify a recommended Phase 2 dose. In addition, the study will also assess the immunologic effect of NKTR-214 on TILs and other immune cells in both blood and tumor tissue, and it will also include TCR repertoire profiling. Dose expansion cohorts are planned to evaluate NKTR-214 in specific tumor types, including melanoma, renal cell carcinoma and non-small cell lung cancer.

The NKTR-214 clinical study is being conducted initially at two primary investigator sites: MD Anderson Cancer Center under Drs. Patrick Hwu and Adi Diab; and Yale Cancer Center, under Drs. Mario Sznol and Michael Hurwitz. Patients and physicians interested in the ongoing NKTR-214 study can visit the "Clinical Trials" section of www.mdanderson.org using identifier 2015-0573 or visit View Source

On June 6, 2016 Principia Biopharma Inc., a private clinical-stage biopharmaceutical company, reported that initial Phase 1 clinical data for its fibroblast growth factor receptor (FGFR) 1-4 inhibitor, PRN1371, was presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Principia Biopharma, JUN 6, 2016, View Source [SID:1234513099]). PRN1371 is an oral, irreversible covalent FGFR 1-4 inhibitor currently being evaluated in a Phase 1 dose escalation trial in patients with solid tumors to be followed by a dose expansion phase.

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Clinical, pharmacokinetic and pharmacodynamic data from the ongoing international, multi-center trial were presented. The data demonstrated consistent pharmacokinetics with high apparent bioavailability, and robust pharmacodynamic impact on surrogate markers of serum phosphate and FGF23 levels. PRN1371 was well tolerated, with no dose limiting toxicities or any major off-target safety signals observed.

The presented poster will be available on the Scientific Publications section of Principia Biopharma’s website at View Source

About FGFR inhibition in cancer

FGFR genetic alterations occur in a wide range of cancers including lung, breast, stomach, liver and bladder. These alterations may be amenable to targeted therapy designed to inhibit the effects of the alteration in driving tumor growth. Highly selective and potent FGFR inhibitors, such as PRN1371, may be able to slow or reverse tumor growth with a lower rate of side effects compared with less selective drugs.

On June 06, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported that the Gynecologic Oncology Group (GOG), now part of NRG Oncology (NRG) will present additional preliminary data from a two-stage Phase 2 study of its lead immunotherapy candidate, axalimogene filolisbac (AXAL), in patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) who have progressed on at least one prior line of systemic therapy (Press release, Advaxis, JUN 6, 2016, View Source [SID:1234513031]).

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These data will be featured at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, Ill., in the Gynecologic Cancer General Poster Session on June 6 at 1:00 PM CT and also in an Oral Poster Discussion Session at 4:45 PM. The poster (abstract #5516), "ADXS11-001 immunotherapy in squamous or non-squamous persistent/recurrent metastatic cervical cancer: Results from stage 1 [and stage 2] of the phase II GOG/NRG-0265 study" and presentation are available at www.advaxis.com. Warner K. Huh, M.D., Professor and Division Director of Gynecologic Oncology and Senior Scientist at the University of Alabama at Birmingham, is the lead author and principal investigator.

GOG/NRG-0265 is a single-arm two-stage, Phase 2 multicenter study (NCT01266460). Stage 1 of the trial enrolled 26 AXAL-treated patients who received up to three doses at 1×109 colony forming units administered in 28 day intervals. Results from Stage 1 demonstrated a twelve-month survival rate of 38.5 percent, which exceeds prior historical GOG trials in this patient population. The twelve-month survival rate among the 69 percent of patients who received the maximum three per protocol doses was 56 percent, with a 12.1-month median overall survival. Safety and efficacy results of Stage 1 met the criteria for the initiation of Stage 2, which was amended for continuous cycles of AXAL (greater than three doses).

Twenty-four patients were treated with AXAL in Stage 2. However, a temporary clinical hold limited overall exposure to the immunotherapy, which necessitated 10 patients who had not progressed to discontinue AXAL treatment. Further, only 12 of the 24 patients received three or more doses. Demographics in the truncated Stage 2 cohort were similar to Stage 1, but a substantially higher proportion of patients were pre-treated with bevacizumab (83 percent (Stage 2) vs. 31 percent (Stage 1)).

At a median follow-up of 8.7 months, these Stage 2 results demonstrate a 42 percent six-month overall survival rate, which increases to 67 percent in those 12 patients who received three or more doses of AXAL. Preliminary results from Stage 2 appear consistent with the promising survival results from Stage 1 in a more heavily bevacizumab pre-treated population.

Investigator assessment of tumor best response showed disease control rates (CR+PR+SD) of 27 percent and 37 percent in Stage 1 and 2, respectively. Of particular note, a patient in Stage 2 experienced a complete response following three doses of AXAL. This patient continues to be followed with no evidence of disease at 11 months. Treatment with AXAL will resume under a compassionate use single-patient IND.

The safety profile across both stages was similar, with primarily grade one and two treatment-related events such as fatigue, chills, fever, nausea. Grade three events (n = 4 in Stage 1) included hypotension and cytokine release syndrome. No grade four or five treatment-related adverse events were observed.

Given the substantial proportion of Stage 2 patients that discontinued treatment with AXAL as a result of the clinical hold, Advaxis and the GOG/NRG agreed to re-enroll a new cohort of Stage 2 patients. The re-enrollment of Stage 2 is expected to commence shortly.

"We are excited about the potential of AXAL to help women with recurrent cervical cancer as there are so few options available," said Daniel J. O’Connor, President and Chief Executive Officer of Advaxis.

The Company and the GOG Foundation plan to commence enrollment to an international Phase 3 adjuvant study, AIM2CERV, for patients with high risk, locally advanced cervical cancer.

About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide. In the U.S., nearly 13,000 new cases are diagnosed, and approximately 4,100 deaths are reported because of cervical cancer. According to the WHO/ICO Information Centre on HPV and Cervical Cancer, about 3.9 percent of women in the U.S. are estimated to harbor high-risk cervical HPV infection at a given time, and 71.7 percent of invasive cervical cancers are attributed to high-risk HPV strains.

About the Gynecologic Oncology Group

The Gynecologic Oncology Group (GOG), now part of NRG Oncology, is a non-profit international organization with the purpose of promoting excellence in the quality and integrity of clinical and basic scientific research in the field of gynecologic malignancies. The GOG is committed to maintaining the highest standards in clinical trials development, execution, analysis and distribution of results. Continuous evaluation of its processes is utilized in order to constantly improve the quality of patient care. The GOG conducts clinical trials for patients with a variety of gynecologic malignancies, including cancers that arise from the ovaries, uterus, cervix, vagina and vulva. General information on many of these trials for medical professionals and the lay public can be obtained from ClinicalTrials.gov.

NRG Oncology is one of four adult cooperative groups funded under the newly structured NCI National Clinical Trials Network. NRG Oncology is comprised of three legacy cooperative groups, the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG).

About Axalimogene Filolisbac

Axalimogene filolisbac (AXAL) is Advaxis’ lead Lm Technology immunotherapy candidate for the treatment of HPV-associated cancers and is in clinical trials for three potential indications: invasive cervical cancer, head and neck cancer, and anal cancer. In a completed randomized Phase 2 study in recurrent/refractory cervical cancer, AXAL showed apparent prolonged survival, objective tumor responses, and a manageable safety profile alone or in combination with chemotherapy, supporting further development of the Company’s Lm Technology. AXAL has Orphan Drug Designations in the U.S. for the treatment of invasive cervical cancer, head and neck cancer and anal cancer.

On June 6, 2016 Seattle Genetics, Inc. (NASDAQ:SGEN) and Astellas Pharma Inc. (TOKYO:4503) reported first clinical data for ASG-15ME and enfortumab vedotin (ASG-22ME) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 51st Annual Meeting being held June 3-7, 2016, in Chicago, IL (Press release, Seattle Genetics, JUN 6, 2016, View Source;p=RssLanding&cat=news&id=2175252 [SID:1234513055]).

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ASG-15ME and enfortumab vedotin are investigational antibody-drug conjugates (ADCs) that consist of monoclonal antibodies designed to deliver microtubule-disrupting agents selectively to tumor cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity. ASG-15ME and enfortumab vedotin target SLITRK6 and Nectin-4, respectively, proteins that are highly expressed in urothelial cancers, particularly bladder cancer. Under the collaboration, the companies are co-developing and plan to globally co-commercialize ASG-15ME and ASG-22ME.

"Bladder cancer is the fifth most common cancer in the U.S., and there have been few treatment advances over the past three decades. For metastatic disease, the five-year survival rate is only 15 percent, representing a significant unmet need to identify additional treatment options," said Len Reyno, M.D., senior vice president and chief medical officer, Agensys, an affiliate of Astellas. "We are pleased to present these first data for ASG-15ME and ASG-22ME in urothelial cancers, which have a particularly high unmet medical need."

"The clinical data from the phase I presented at ASCO (Free ASCO Whitepaper) from the ASG-15ME and enfortumab vedotin programs in heavily pretreated metastatic bladder cancer patients show a manageable safety profile along with objective response rates that are higher than historical rates seen with taxanes," said Jonathan Drachman, M.D., chief medical officer and executive vice president, Research and Development at Seattle Genetics. "We will continue enrolling patients in the ongoing phase I clinical trials to determine the recommended dose for further development."

The following data were presented during poster sessions on Monday, June 6, 2016:

Anti-Tumor Activity, Safety and Pharmacokinetics (PK) of AGS15E (ASG-15ME) in a Phase I Dose Escalation Trial in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #4532, poster presentation on Monday, June 6, 2016)
Data were reported from 49 patients with metastatic urothelial cancer. The median age of patients was 64 years. Of the 49 patients, 48 patients (98 percent) had undergone treatment with a platinum-based chemotherapy regimen, including 33 patients (67 percent) with a cisplatin-based regimen, and 14 patients (29 percent) who had progressed on or after treatment with checkpoint inhibitors. Twenty-nine patients (59 percent) had received two or more prior systemic therapies. The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of ASG-15ME as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received ASG-15ME at 0.1 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. Key findings include:
Of the 43 patients evaluable for response, 14 patients (33 percent) had an objective response, including one patient (two percent) who achieved a complete response and 13 patients (30 percent) who achieved a partial response. While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 27 patients (63 percent), defined as achieving complete remission, partial remission or stable disease.
In 16 patients treated at the 1.0 mg/kg dose level, seven patients (44 percent) had an objective response. In five patients treated at the 1.25 mg/kg dose level, two patients (40 percent) had an objective response.
In the 13 patients whose cancer had metastasized to the liver, four patients (31 percent) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis.
In the 14 patients who had previously been treated with checkpoint inhibitors, five patients (36 percent) achieved a partial remission.
The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were fatigue (43 percent) and nausea (20 percent). Peripheral neuropathy was observed in 10 patients (19 percent) at Grade 1 and six patients (11 percent) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported.
In the study, eight patients developed ocular symptoms with corneal abnormalities. The majority of patients were managed with dose reductions and recovered.
Enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.
Anti-Tumor Activity, Safety and Pharmacokinetics (PK) of ASG-22CE (ASG-22ME; enfortumab vedotin) in a Phase I Dose Escalation Trial in Patients (Pts) with Metastatic Urothelial Cancer (mUC) (Abstract #4533, poster presentation on Monday, June 6, 2016)
Data were reported from 44 patients with metastatic urothelial cancer. The median age of patients was 66.5 years. Of the 44 patients, 43 patients (98 percent) had undergone treatment with a platinum-based chemotherapy regimen, including 30 patients (68 percent) with a cisplatin-based regimen, and 12 patients (27 percent) who had progressed on or after treatment with checkpoint inhibitors. Twenty-eight patients (64 percent) had received two or more prior systemic therapies.
The primary endpoints of the ongoing clinical trial are to evaluate escalating doses, pharmacokinetics and safety of enfortumab vedotin as a monotherapy. In addition, the trial is evaluating antitumor activity, objective response rate and disease control rate. In this dose-escalation study, patients received enfortumab vedotin at 0.5 to 1.25 mg/kg weekly for three of every four week cycles. Key findings include:
Of the 36 patients evaluable for response, 10 patients (28 percent) achieved a partial response. While the study is ongoing, preliminary estimates show median duration of response at 16.1 weeks. Disease control was achieved for 25 patients (69 percent), defined as achieving complete remission, partial remission or stable disease.
In eight patients treated at the 1.25 mg/kg dose level, four patients (50 percent) had an objective response.
In the 10 patients whose cancer had metastasized to the liver, four patients (40 percent) achieved a partial remission. Bladder cancer that metastasizes to the liver typically has a poor prognosis.
In the 12 patients who had previously been treated with checkpoint inhibitors, three patients (25 percent) achieved a partial remission.
The most common treatment-related adverse events of any grade occurring in 15 percent or more of patients were pruritis and nausea (30 percent each), fatigue (25 percent), diarrhea (21 percent) and rash (18 percent). Peripheral neuropathy was observed in 11 patients (19 percent) at Grade 1 and three patients (five percent) at Grade 2. No Grade 3 or 4 peripheral neuropathy was reported.
In the study, two patients developed ocular symptoms with corneal abnormalities. The patients were managed with dose reductions and/or steroid eye drops.
Enrollment is ongoing at 1.0 and 1.25 mg/kg to identify a recommended dose for future studies.
The ASG-15ME and enfortumab vedotin phase I clinical trials are ongoing to identify a recommended dose for future clinical evaluation. More information about the clinical trials, including enrolling centers, is available by visiting www.clinicaltrials.gov.

About Bladder Cancer

Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. Most bladder cancers start in the innermost lining of the bladder, which is called the urothelium or transitional epithelium. Urothelial carcinoma, also known as transitional cell carcinoma (TCC), is the most common type of bladder cancer. Urothelial carcinoma starts in the urothelial cells that line the inside of the bladder.

While patients with early stage bladder cancer are treated with curative intent, outcomes are poor for patients diagnosed with locally advanced or metastatic disease. For the approximately 10 percent of patients with urothelial bladder cancer whose initial diagnoses occur when they have metastatic disease, the average five-year survival is approximately 15 percent. According to the American Cancer Society, in 2016 approximately 77,000 people will be diagnosed and more than 16,000 will die from urothelial bladder cancer.

About ASG-15ME and Enfortumab Vedotin

ASG-15ME is an investigational antibody-drug conjugate (ADC) composed of an anti-SLITRK6 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E (MMAE), using Seattle Genetics proprietary, industry-leading linker technology. ASG-15ME is the first and only agent to target SLITRK6, a transmembrane protein identified as an ADC target by Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that ASG-15ME effectively binds to target cells, internalizes and induces cell-killing activity.

Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary, industry-leading linker technology. Enfortumab vedotin is the first and only agent to target Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys, which is expressed on many solid tumors. Preclinical data demonstrate that enfortumab vedotin effectively binds to target cells, internalizes and induces cell-killing activity.