The first patient has officially been dosed with investigational anti-Dickkopf-1 antibody (

) plus tislelizumab (BGB-A317) with or without chemotherapy as part of the ongoing phase 2a DisTinGuish study (NCT04363801) in patients with gastric or gastroesophageal junction (GEJ) cancer.

"Dosing of the first patient in the DisTinGuish study is a key milestone for the DKN-01 development program," said Cynthia Sirard, MD, chief medical officer of Leap Therapeutics the developer of DKN-01. "We are excited to have the opportunity to combine DKN-01 with tislelizumab due to the promising signals in a DKK1 biomarker-defined population of esophagogastric cancer patients. We look forward to working closely alongside BeiGene to evaluate this potential new combination therapy for a patient population with a high global unmet medical need."

 in September 2020 for the treatment of patients with gastric and GEJ adenocarcinoma with a high-risk of DKK1 tumor expression, as well as those who have progressed following fluoropyrimidine- and platinum-containing chemotherapy, and HER2/neu targeted therapy.

 Previous data showed that in the phase 1/2 P102/KEYNOTE-731 trial, DKN-01 plus pembrolizumab demonstrated a median PFS of more than 22 weeks in 10 evaluable patients, while the median OS was approximately 32 weeks. Additionally, the ORR was 50% and the DCR was 80%. In low DKK1-expressing patients, the median PFS was 6 weeks, and the median OS and DCR rate was was 17 weeks and 20%, respectively.

Thenonrandomized, open-label, multicenter phase 2a, study is examining the combination of DKN-01 and tislelizumab with or without chemotherapy as either a first- or second-line treatment in patients with inoperable, locally advanced gastric or GEJ adenocarcinoma.

The study is conducted in 2 parts—parts A and B, both of which will be enrolled concurrently—accruing up to 72 patients aged 18 years or older with measurable disease. In part A of the study, patients will receive a frontline treatment consisting of 300 mg of intravenous DKN-01 on days 1 and 15, 200 mg of tislelizumab on day 1, 130 mg/m2 of oxaliplatin on day 1, and oral capecitabine (Xeloda; 1000 mg/m2) on days 1 to 15 of each 21-day cycle.

In order to be eligible for this portion of the trial, patients could not have undergone prior systemic therapy for locally advanced or metastatic disease. That being said, prior adjuvant or neoadjuvant therapy was permitted, provided that the treatment was completed without disease recurrence for a minimum of 6 months.

In both parts of the study, the safety, tolerability, and efficacy of the combination will be evaluated. The combination will be administered in repeating 21-day cycles until those enrolled on the trial either meet the criteria for discontinuation of treatment or are no longer receiving clinical benefit from the regimen.

Part B focuses on treatment in the second-line setting, with 1 cohort of patients receiving 300 mg of DKN-01 on days 1 and 15 and 200 mg of tislelizumab on day 1 of each 21-day cycle, while a second cohort received a 600 mg dose of DKN-01. In this part of the trial, patients arerequired to have a DKK1-high disease of ≥35 and could have received 1 prior systemic therapy for locally advanced or metastatic disease. Much like part A, neoadjuvant and adjuvant therapy were allowed.

The primary end point of the study is safety and tolerability, with key secondary end points consisting of ORR, duration of response, progression-free survival (PFS), OS, duration of clinical benefit, DCR, and duration of response.

Leap Therapeutics and BeiGene announce first patient dosed in study of DKN-01 in combination with tislelizumab for the treatment of metastatic gastric or gastroesophageal junction cancer. News release. Nasdaq Investors. September 21, 2020. Accessed September 21, 2020. 

Leap Therapeutics Announces FDA Fast Track Designation granted to DKN-01 for the treatment of gastric and gastroesophageal junction cancer. News release. Leap Therapeutics. September 24, 2020. Accessed October 7, 2020. 

A Study of DKN-01 in combination with tislelizumab ± chemotherapy in patients with gastric or gastroesophageal cancer (DisTinGuish). ClinicalTrials.gov. Updated August 25, 2020. Accessed October 7, 2020. 

Articles

The first patient has officially been dosed with investigational anti-Dickkopf-1 antibody plus tislelizumab with or without chemotherapy as part of the ongoing phase 2a DisTinGuish study (NCT04363801) in patients with gastric or gastroesophageal junction cancer. 

DisTinGuish Trial Doses First Patient With Investigational Dickkopf-1 Antibody DKN-01 Plus Tislelizumab in Gastric/GEJ Cancer

An ongoing, collaborative clinical trial (NCT03947385) between IDEAYA Biosciences, Inc. and Pfizer has been expanded to evaluate the investigational protein kinase C (PKC) inhibitor IDE196 in combination with the cMET multikinase inhibitor crizotinib (Xalkori) for patients with 

–mutated solid tumors, including metastatic uveal melanoma (MUM), skin melanoma, lung cancer, and colorectal cancer (CRC), according to IDEAYA Biosciences.

IDEAYA Biosciences, Inc. will sponsor the trial, while Pfizer, which has exclusive worldwide rights to crizotinib, will supply crizotinibthe TKI. Pfizer has exclusive worldwide rights to crizotinib. The IDE196/crizotinib arm of the trial is set to be initiated between late 2020 and early 2021.

“We are excited to expand our agreement with Pfizer to evaluate the clinical combination of IDE196 and crizotinib in MUM and other solid tumors with 

 mutations,” said Mick O'Quigley, vice president and head of development operations of IDEAYA Biosciences.

IDEAYA Biosciences, Inc. identified cMET expression or activation has been identified as a potential prognostic biomarker of IDE196 treatment in patients with MUMmetastatic uveal melanoma. Additionally, the PKC inhibitor was found to demonstrated preclinical synergistic activity with crizotinib in this patient population.

 mutations,” said Mick O'Quigley, vice president and head of development operations of IDEAYA Biosciences, Inc. in the press release.

Mark Lackner, PhD, senior vice president and head of biology and translation sciences at IDEAYA Biosciences, Inc, added, “Through our translational research we have identified cMET expression as a potential biomarker, and we are excited to explore this rational combination between IDE196 and crizotinib clinically,” said Mark Lackner, PhD, senior vice president and head of biology and translation sciences at IDEAYA Biosciences.”

The initial collaboration and supply agreement between IDEAYA Biosciences, Inc. and Pfizer induced an expansion of the phase 2 portion of the trial and formed a joint development committee (JDC) between the companies. The JDC means that the parties will make joint decisions and share data regarding the results of the clinical trial. The companies will enter into good faith negotiations should clinical data obtained from the trial be used to obtain regulatory approvals or label changes.

The initial agreement included an ongoing study evaluating IDE-196 in combination with the MEK inhibitor binimetinib (Mektovi). Dosing for the IDE196/binimetinib portion of the study commenced in July 2020 for patients with metastatic uveal melanoma, according to the news release.

Prior to this,Previously, IDE196 was evaluated as monotherapy in an ongoing, phase 1, dose-escalation basket trial (NCT02601378). Data from the study, which were presented during the 2019 AACR Annual Meeting, reported an overall response rate of 13% (95% CI, 4%-31%) and a disease control rate of 73% among 30 patients treated with IDE196.

Moreover, 4 patients achieved a partial response (PR), while an additional 2 patients had unconfirmed PRs.

All patients had MUM metastatic uveal melanoma and were treated with 200 mg, 300 mg, or 400 mg of twice-daily IDE196 twice daily.

The According to a press release, the 400-mg dose, given (with as a one-weekly 200-mg, twice-daily run-in) was selected as the recommended phase 2 dose of IDE196.5 With this dose, patients observed an approximately 44% higher average steady state exposure of free IDE196 (area under the curvefree) and an approximate 40% higher trough concentration of IDE196 compared with the 300-mg, twice-daily dose.

As of May 2019, 5 patients remained on IDE196 for longer than 18 months and 3 were on for more than 2 years.

Regarding safety with IDE196, the most frequently observed dose-limiting toxicity was transient hypotension, which was well managed.

IDE196 continues is also to being evaluated as monotherapy in an ongoing 

non-MUM basket trial, as well as in the combination trials with binimetinib and crizotinib.

Ideaya and Pfizer to test doublet therapy in certain solid tumors. News release. Seeking Alpha. September 24, 2020. Accessed October 12, 2020. 

IDEAYA and Pfizer expand clinical trial collaboration and supply agreement to evaluate clinical combination of IDE196 and crizotinib in solid tumors harboring GNAQ or GNA11 mutations. News release. Seeking Alpha. September 24, 2020. Accessed October 12, 2020. 

Ideaya teams up with Pfizer in cancer study. News release. Seeking Alpha. March 18, 2020. Accessed October 12, 2020. 

Carlino MS, McKean M, Orloff M, et al. A phase 1/2 study of IDE196 in patients with metastatic uveal melanoma or solid tumors harboring 

 fusions. Presented at: the 16th International Congress of the Society for Melanoma Research Congress; November 20-23, 2019. Accessed October 12, 2020. 

IDEAYA Biosciences Announces IDE196 Monotherapy Phase 2 Dose Selection and Clinical Program Update. News release. Seeking Alpha. March 18, 2020. Accessed October 12, 2020. 

An ongoing, collaborative clinical trial has been expanded to evaluate the investigational protein kinase C inhibitor IDE196 in combination with the multikinase inhibitor crizotinib (Xalkori) for patients with GNAQ- or GNA11-mutated solid tumors, including metastatic uveal melanoma , skin melanoma, lung cancer, and colorectal cancer.

IDE196/Crizotinib Combo Under Exploration in GNAQ/11+ Solid Tumors

Gilead Sciences’ acquisition of Immunomedics, the manufacturer of sacituzumab govitecan-hziy (Trodelvy), is expected to advance the development of the antibody-drug conjugate (ADC) not only across additional types of breast cancer beyond triple-negative disease, but also in other solid tumors.

“The acquirement of Immunomedics will be very meaningful for further development of this agent. With Gilead’s resources, there will be many opportunities to move sacituzumab govitecan into larger studies in earlier disease settings,” said Sara M. Tolaney, MD, MPH, an author on the phase 1/2 IMMU-132-01 trial (NCT01631552) that led to the conditional approval of the ADC,

FDA granted sacituzumab govitecan accelerated approva

l for use in adults with metastatic triple-negative breast cancer (TNBC) who received at least 2 prior therapies for metastatic disease.

 validated the benefit of the agent in this patient population, demonstrating a 59% reduction in the risk of disease progression or death compared with physician’s choice of single-agent chemotherapy.

Sacituzumab govitecan is specifically approved for third-line metastatic TNBC, but has shown promise in earlier stages of disease,

 supporting further study of the Trop-2–directed intervention in more immediate lines of treatment.

“There is so much potential for this agent to be able to move earlier in the metastatic setting and have a bigger role in the early-disease setting, and I think having Gilead develop this agent and move it into these settings is incredible,” said Tolaney, who is also the director of Clinical Trials in Breast Oncology and the associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute.

After closing on Immunomedics, Gilead will initiate several mid- and late-stage studies examining the efficacy of sacituzumab govitecan as a single agent and in combination with other therapies. Gilead has yet to disclose the disease settings in which these investigations will proceed.

 When initiated, these trials will broaden the portfolio of studies examining the safety of the ADC and its anticancer activity in various malignancies.

Ongoing research efforts include the phase 3 TROPICS-02 study (NCT03901339) of sacituzumab govitecan in third-line hormone receptor–positive, HER2-negative breast cancer and the phase 2 open-label TROPHY U-01 trial (NCT03547973) in metastatic urothelial carcinoma. Final results from the metastatic urothelial cancer cohort of the 

 were presented during the 2020 ESMO Virtual Congress and confirmed the clinical activity of sacituzumab govitecan in patients with heavily pretreated disease who progressed on platinum chemotherapy and

immunotherapy. The ADC is also the focus of the phase 3 TROPiCS-04 confirmatory trial (NCT04527991) that is being done in patients with urothelial carcinoma.

Sacituzumab govitecan is also under investigation in non–small cell lung cancer, recurrent glioblastoma, endometrial carcinoma, and metastatic castration-resistant prostate cancer, among other solid tumors. The breadth of trials evaluating the ADC is a testament to Immunomedics’ efforts to advance the agent, according to Tolaney. “I think Immunomedics has done a great job developing sacituzumab govitecan from a first-in-human basket study,” Tolaney said.

The news of the acquisition comes after Immunomedics’ August 5, 2020 announcement that it planned to submit a supplemental biologics application for the full approval of sacituzumab govitecan in metastatic TNBC during the fourth quarter of 2020.

Immunomedics is reportedly also on track to file for regulatory approval of the agent in Europe in the first half of 2021, according to Gilead. Under the acquisition, sacituzumab govitecan will join Gilead’s portfolio of approved and late-stage therapies for hematological malignancies, which currently includes axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), and magrolimab.

Gilead to acquire Immunomedics. News release. Gilead Sciences, Inc. September 13, 2020. Accessed October 8, 2020. https://bit.ly/34GW8eR.

FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. News release. FDA. April 22, 2020. Accessed October 8, 2020. https://bit.ly/33EFq0i.

Bardia A, Tolaney SM, Loirat D, et al. ASCENT: A randomized phase 3 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA17.

Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based regimens and checkpoint inhibitors (CPI). Presented at 2020 ESMO Virtual Congress; Virtual. Abstract LBA24.

Immunomedics reports second quarter 2020 results and provides corporate update. News release. Immunomedics. August 5, 2020. Accessed October 8, 2020. https://bit.ly/3nwuyJK.

Gilead Sciences’ acquisition of Immunomedics, the manufacturer of sacituzumab govitecan-hziy, is expected to advance the development of the antibody-drug conjugate not only across additional types of breast cancer beyond triple-negative disease, but also in other solid tumors. 

Immunomedics Acquisition Transfers Development of Sacituzumab Govitecan to Gilead Sciences

Pipeline Report: October 2020

Saad Z. Usmani, MD, FACP, chief of Plasma Cell Disorders and director of Clinical Research in Hematologic Malignancies, Levine Cancer Institute, Atrium Health, discusses future research directions with the combination of nirogacestat (PF-03084014) and teclistamab (JNJ-64007957) in patients with relapsed/refractory multiple myeloma.

SpringWorks Therapeutics announced it would be partnering with Janssen to open a phase 1 trial examining the combination of these agents

. The most important objective of the trial is to evaluate the safety of the combination, Usmani says. Investigators estimate that the safety data from this trial will be generated and presented to the scientific community within 1 year, Usmani explains.

If the combination demonstrates positive safety and is shown to enhance clinical activity, it is likely that the next steps with this research would be to examine nirogacestat and teclistamab in combination with other therapies, Usmani concludes.

Videos

Saad Z. Usmani, MD, FACP, discusses future research directions with the combination of nirogacestat and teclistamab in patients with relapsed/refractory multiple myeloma.


Pipeline Report: October 2020

Articles

DisTinGuish Trial Doses First Patient With Investigational Dickkopf-1 Antibody DKN-01 Plus Tislelizumab in Gastric/GEJ Cancer

IDE196/Crizotinib Combo Under Exploration in GNAQ/11+ Solid Tumors

Videos

Dr. Usmani on Future Research Directions for Nirogacestat/Teclistamab in Myeloma