Celldex Therapeutics (CLDX) presented two programs at the 2018 American Society of Clinical Oncology Annual Meeting. Data from the Phase 1/2 study of Celldex’s varlilumab, a CD27 targeting investigational immune-activating antibody, and Bristol-Myers Squibb’s (BMY) Opdivo, or nivolumab, an anti-PD1 immunotherapy, for patients with ovarian cancer and colorectal cancer, were presented. In addition, an overview of the Phase 2 study of the anti-ErbB3 antibody CDX-3379 in combination with Erbitux in advanced head and neck squamous cell cancer was presented in a “clinical trials in progress” poster session. Varlilumab was featured in an oral presentation that highlighted the ongoing Phase 2 study of varlilumab in combination with Opdivo. The Phase 1/2 study includes cohorts in ovarian cancer, colorectal cancer, head and neck squamous cell carcinoma, renal cell carcinoma and glioblastoma, with data from ovarian cancer and colorectal cancer patients included in the presentation. The majority of patients enrolled in the study had baseline tumors that were mostly “cold” with low expectation of responding to checkpoint inhibition therapy. The combination was well tolerated at all varlilumab dose levels tested. One patient with PD-L1 negative, MSI-high disease experienced a confirmed partial response in the Phase 2 study portion and continues on treatment. Of note, a patient with PD-L1 negative disease, initially considered MMR proficient as determined by standard screening laboratory analysis, achieved a near complete response in the Phase 1 portion of the study, which now continues at 35 months. As part of this study, an additional molecular analysis was conducted on this patient’s tumor. The tumor had a high mutational burden and mutations in genes regulating DNA repair, which together likely contributed to the response. DCR was 20%. CDX-3379 was featured in a “clinical trials in progress” poster presentation that highlighted the ongoing Phase 2 study of CDX-3379, a human monoclonal antibody designed to block the activity of ErbB3, in combination with Erbitux in patients with human papillomavirus negative, Erbitux-resistant, advanced head and neck squamous cell carcinoma. The proposed mechanism of action for CDX-3379 sets it apart from other drugs in development in this class due to its ability to block both ligand-independent and ligand-dependent ErbB3 signaling by binding to a unique epitope. It has a favorable pharmacologic profile, including a longer half-life and slower clearance relative to other drug candidates in this class. The multicenter, open-label, Simon two-stage design study is expected to enroll approximately 27 patients. The primary objective of the study is objective response rate. Secondary objectives include assessments of clinical benefit response, duration of response, progression-free survival and overall survival, and safety and pharmacokinetics associated with the combination. Four clinical trial sites are currently open to enrollment, and Celldex is targeting to complete enrollment to the first stage of the study by the end of the third quarter of 2018. The company continues to explore potential other opportunities in additional indications where ErbB3 is believed to play a role.
Sunday, June 3, 2018
AstraZeneca, MedImmune meet primary endpoints in Phase 3 leukemia trial
AstraZeneca and MedImmune, its global biologics research and development arm, presented results from the Phase III ‘1053’ clinical trial that evaluated moxetumomab pasudotox in 80 patients with relapsed or refractory hairy cell leukemia who had received at least two prior lines of therapy. Moxetumomab pasudotox, an investigational anti-CD22 recombinant immunotoxin, showed a 75% objective response rate, a 41% complete response rate, and a 30% durable CR rate. The majority of patients with a complete response had a durable response and achieved a negative minimal residual disease status. The primary endpoint of the trial was durable CR, which is defined as CR with HR for greater than180 days. The median time to HR was 1 month. The most frequent treatment-related adverse events were nausea, peripheral edema, headache, and pyrexia; 8% had infections and 3% had neutropenia deemed treatment-related. Three patient deaths occurred, none of which were determined to be treatment-related. Treatment-related AEs leading to discontinuation were hemolytic uremic syndrome, capillary leak syndrome, and increased blood creatinine. Seven patients had CLS and seven had HUS; this includes four patients who had both CLS and HUS. CLS and HUS were manageable and reversible. In April 2018, AstraZeneca announced that the Food and Drug Administration accepted the Biologics License Application for moxetumomab pasudotox for the treatment of adult patients with HCL who have received at least two prior lines of therapy. The BLA is based on results from the Phase III ‘1053’ clinical trial. The FDA has granted Priority Review status with a Prescription Drug User Fee Act action date set for the third quarter of 2018.
AbbVie announced positive data from Phase 2 leukemia combo study
AbbVie announced positive data from the Phase 2 CAPTIVATE study evaluating IMBRUVICA, or ibrutinib, in combination with VENCLEXTA in previously-untreated chronic lymphocytic leukemia/small lymphocytic lymphoma patients. Early results of the combination oral regimen suggest promising activity in treatment-naive CLL/SLL with 77% of the first 30 patients achieving responses with no detectable minimal residual disease after six cycles of the combination therapy. MRD is determined by measuring the number of cancer cells remaining and helps confirm depth of remission. The first 14 CLL/SLL patients to complete the clinical trial combination therapy of 12 cycles achieved responses with no detectable MRD in approximately nine out of 10 patients, with 93% achieving MRD negativity when measuring in peripheral blood and 86 percent with MRD negativity when measuring in the bone marrow. The most common AEs were diarrhea, fatigue, nausea, headache, upper respiratory tract infection and arthralgia. Grade 3 or higher AEs – occurring in greater than or equal to 3% patients – were neutropenia, hypertension, diarrhea and thrombocytopenia. No clinical tumor lysis syndrome occurred and lab TLS was seen in 1 of 164 patients. In treated patients with baseline LDi 5 cm or greater, LDi decreased to less than 5 cm in 43 of 53 patients after ibrutinib lead-in. TLS risk shifted from high to medium/low in 36 of 40 patients, and overall, the proportion of high-risk TLS decreased from 24% at baseline to 3% after ibrutinib lead-in.
FDA wants to shorten new drug monopolies to cut costs
In an effort to increase competition and bring down prescription drug prices, FDA Commissioner Scott Gottlieb speaking at the American Society of Clinical Oncology Annual Meeting said he wants to speed approval times for rivals to promising new first-to-market medicines, according to Reuters. The U.S. Food and Drug Administration chief has made a commitment to speeding up approvals of cheap generic medicines, the report added.
Merck, Eisai detail expanded use of combo med for several cancers
Eisai and Merck announced results from presentations of new data and analyses of LENVIMA, an orally available kinase inhibitor discovered by Eisai, in combination with Merck’s anti-PD-1 therapy, KEYTRUDA, in four different tumor types: unresectable hepatocellular carcinoma, squamous cell carcinoma of the head and neck, advanced renal cell carcinoma, and advanced endometrial carcinoma. LENVIMA and KEYTRUDA are not approved for use in combination in any cancer types today. Early phase results from Study 116/KEYNOTE-524 support further investigation in unresectable HCC. Study 116/KEYNOTE-524 is a Phase 1b open-label, single-arm multicenter study evaluating the tolerability and safety of the combination of LENVIMA and KEYTRUDA in patients with unresectable HCC, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, and ECOG performance status of 0 or 1. The primary endpoint was safety; secondary and exploratory endpoints included overall survival, objective response rate, progression-free survival and time to progression using modified Response Evaluation Criteria in Solid Tumors criteria. Tumor assessments of complete or partial response were confirmed greater than or equal to four weeks after initial response. Part 1 evaluated tolerability by assessing dose-limiting toxicities during the first cycle of treatment in patients for whom no other appropriate therapy was available. After tolerability was confirmed, additional patients with no prior systemic therapy for unresectable HCC were enrolled. The expansion part of the study will evaluate ORR and duration of response as measured by mRECIST.
#ASCO18: Phase 3 trial: Many advanced kidney cancers don’t need surgery
A randomized phase III clinical trial showed that many people with advanced kidney cancer can avoid surgery to remove the kidney (nephrectomy), without compromising survival. The median overall survival for people who received only the targeted therapy sunitinib (Sutent®) was 18.4 months, compared to 13.9 months for those who received surgery followed by sunitinib, the current standard of care.
These findings will be presented in ASCO’s Plenary Session, which features four studies deemed to have the greatest potential impact on patient care, out of the more than 5,800 abstracts featured as part of the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting.
“Until now, nephrectomy has been considered the standard of care for patients with kidney cancer who have metastatic disease when the cancer is first diagnosed. These cases account for about 20% of all kidney cancers worldwide,” said lead study author Arnaud Mejean, MD, a urologist at the Department of Urology, Hôpital Européen Georges-Pompidou – Paris Descartes University in Paris, France. “Our study is the first to question the need for surgery in the era of targeted therapies and clearly shows that surgery for certain people with kidney cancer should no longer be the standard of care.”
In addition to putting patients at risk for complications, including blood loss, infection, pulmonary embolism, and heart problems, nephrectomy delays medical treatment for people with advanced kidney cancer for weeks. In some cases, the cancer worsens so rapidly during this delay that there is no time to start systemic treatment.
About the Study: The CARMENA trial enrolled 450 patients with synchronous metastatic renal cell carcinoma (mRCC), meaning that metastases were already present when kidney cancer was first diagnosed. An estimated 40,000 to 50,000 people each year are diagnosed with this type of cancer.1,2
The patients were randomly assigned to receive surgery followed by sunitinib or sunitinib alone. In the surgery group, patients started sunitinib 4-6 weeks after surgery to allow time for recovery from surgery.
Key Findings: Patients were followed for a median time of 50.9 months. Survival was not worse with sunitinib alone than with surgery and sunitinib. This was true for the study population as a whole (median survival was 18.4 months without surgery vs. 13.9 months with surgery), as well as for subgroups with an intermediate (median survival was 23.4 months vs. 19 months) and poor prognosis (median survival was 13.3 months vs. 10.2 months) groups.
The difference in median survival seems to suggest a greater benefit with sunitinib alone. However, this cannot be concluded, as this trial was not designed to prove that one treatment is superior to the other, noted Dr. Mejean.
The rate of tumor response to therapy (tumor shrinkage) was the same in the two treatment groups (27.4% and 29.1%) and the median time until the cancer worsened was slightly longer for patients who received sunitinib alone compared with those who also had surgery (8.3 months vs. 7.2 months). Clinical benefit was experienced by 47.9% of patients treated with sunitinib only, compared with 36.6% of patients treated by surgery and sunitinib.
The authors remarked that kidney surgery is still the gold standard for people who do not need systemic therapy, such as those with only one metastasis. Those patients were not included in this clinical trial.
Next Steps: Some patients in the study had a very good response to sunitinib alone and received surgery after completing systemic treatment. The researchers plan to continue following outcomes in these patients, as well as in other subgroups of study participants. Genomic research on tumor tissue collected on the study is underway.
This study received funding from PHRC (French governmental grants for clinical research).
Study at a Glance
Disease: Metastatic Kidney Cancer
Trial Phase, Type: Phase III, Randomized
Patients on Trial: 450
Intervention Tested: Surgery followed by sunitinib (standard of care) vs. sunitinib alone
Primary Finding: mOS 13.9 months with standard of care vs. 18.4 months with sunitinib alone
Secondary Finding(s): mPFS 8.3 months with standard of care vs. 7.2 months with sunitinib alone
Disease: Metastatic Kidney Cancer
Trial Phase, Type: Phase III, Randomized
Patients on Trial: 450
Intervention Tested: Surgery followed by sunitinib (standard of care) vs. sunitinib alone
Primary Finding: mOS 13.9 months with standard of care vs. 18.4 months with sunitinib alone
Secondary Finding(s): mPFS 8.3 months with standard of care vs. 7.2 months with sunitinib alone
References:
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed July 16, 2013.
2. The epidemiology of renal cell carcinoma. Ljungberg B1, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, Kiemeney LA. Eur Urol. 2011 Oct;60(4):615-21.
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr. Accessed July 16, 2013.
2. The epidemiology of renal cell carcinoma. Ljungberg B1, Campbell SC, Choi HY, Jacqmin D, Lee JE, Weikert S, Kiemeney LA. Eur Urol. 2011 Oct;60(4):615-21.
#ASCO18: Prostate cancer combo med progresses to Phase 2
Abiraterone and enzalutamide improve survival for patients with metastatic castration resistant prostate cancer1,2. Unfortunately, 20-40% of patients have primary resistance abiraterone or enzalutamide, and essentially all patients develop secondary resistance3. Various mechanisms have been postulated for why patients develop cross resistance – one of which being the presence of androgen receptor splice variants. In particular, androgen-receptor splice variant 7 messenger RNA (AR-V7) has been well defined by as a variant which is associated with resistance to enzalutamide and abiraterone. Antonarakis and colleagues demonstrated prospectively that in a cohort of patients receiving enzalutamide, 53% of AR-V7 negative patients had a response compared to 0% of AR-V7 positive patients3.
In this small phase I study, Dr. Pan and colleagues utilized niclosamide in combination with abiraterone in patients with progressive castration resistant prostate cancer. Niclosamide, a salicylamide derivative, was originally an anti-helminthic drug but more recently has been explored in variety of malignancies including HCC, colon cancer, and ovarian cancer4-7. In ovarian cancer cell lines, niclosamide may impact the Wnt/beta-catenin, mTOR, and STAT3 pathways.
6 patients were treated with niclosamide/PDMX1001 at a dose of 1600 mg TID without any dose limiting toxicities. This is the dose that will be used as the phase II dose. At this dose, the trough was at least three times the target level of niclosamide. Of the 6 patients, two have had undetectable PSAs for 16 cycles with ongoing activity and two patients have a partial response with more than 50% PSA decline. One limitation to this study is the lack of a control arm – patients were compared against historical controls. A second limitation to this study is that abiraterone is highly active in this patients and it difficult to say if these patients would have had the same response without niclosamide.
The next step will be to test if niclosamide will be effective in the population of patients who have disease refractory to enzalutamide or abiraterone. Per Dr. Pan, the phase II study began enrolling patients last week and they will plan to enroll only patients who have progressed on enzalutamide.
Presented By: Chong-xian Pan, MD, PhD. University of California Davis Comprehensive Cancer Center
Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealdJasonZhu at the 2018 ASCO Annual Meeting – June 1-5, 2018 – Chicago, IL USA
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