On July 6, 2019 Array BioPharma Inc. (Nasdaq: ARRY) reported the presentation of results from the Phase 3 BEACON CRC trial evaluating the combination of BRAFTOVI (encorafenib), a BRAF inhibitor, MEKTOVI (binimetinib), a MEK inhibitor, and ERBITUX (cetuximab), an anti-EGFR antibody (BRAFTOVI Triplet), in patients with advanced BRAFV600E-mutant metastatic colorectal cancer (mCRC), following one or two lines of therapy (Press release, Array BioPharma, JUL 6, 2019, View Source [SID1234537387]). Data presented included primary and secondary endpoints, waterfall plots describing tumor reduction, subgroup analyses, and exploratory analyses comparing overall survival (OS) of the BRAFTOVI Triplet and BRAFTOVI Doublet (BRAFTOVI and cetuximab) in a subset of patients with mature follow-up, including the first 331 randomized patients, as well as safety and tolerability.

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Results showed that BRAF-mutant mCRC patients treated with the BRAFTOVI Triplet combination demonstrated a statistically significant improvement in OS (9.0 months vs. 5.4 months, [HR 0.52, (95% CI 0.39-0.70), p<0.0001]) and objective response rate (ORR) (26.1% vs. 1.9%, p<0.0001, as assessed by Blinded Independent Central Review (BICR)) compared to cetuximab plus irinotecan-containing regimens (Control). Median progression-free survival (mPFS) for patients treated with the BRAFTOVI Triplet was 4.3 months [HR 0.38, (95% CI 0.29, 0.49), p<0.0001] compared to 1.5 months observed with the Control arm.

These data were presented in an oral presentation on Saturday, July 6, at the ESMO (Free ESMO Whitepaper) 21stWorld Congress on Gastrointestinal Cancer in Barcelona, Spain.

"It’s exciting to see the interim analysis results from the potentially practice-changing BEACON CRC trial, which demonstrated a significant improvement in outcomes compared to available standard of care options for patients with BRAFV600E-mutant metastatic colorectal cancer," said Scott Kopetz, M.D., Ph.D., FACP, Associate Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. "These data add to the body of evidence supporting the BRAFTOVI Triplet as a potential new standard of care regimen for this patient population, who currently have limited treatment options available."

The interim analysis also showed an improvement in secondary efficacy endpoints. Patients treated with the BRAFTOVI Doublet demonstrated a statistically significant improvement in OS (median 8.4 months vs. 5.4 months, [HR 0.60, 95% CI (0.45-0.79), p=0.0003]) and ORR (20.4% vs. 1.9%, p<0.0001, per BICR) compared to Control. Further, mPFS for patients treated with the BRAFTOVI Doublet was 4.2 months [HR 0.40, 95% (CI 0.31-0.52), p<0.0001] versus 1.5 months with Control.

A descriptive comparison of the BRAFTOVI Triplet to the BRAFTOVI Doublet demonstrated a positive trend across endpoints including ORR and OS [HR 0.79, 95% CI (0.59-1.06)].

The control arm of the BEACON CRC trial was consistent with past reported studies and historical data across efficacy endpoints, underscoring that patients with BRAF-mutant mCRC generally have a poor prognosis with current available treatments. Currently there are no FDA-approved therapies specifically indicated for this high unmet need population. [1-13] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and V600E is the most common mutation. [1-3,12-14]

The BRAFTOVI Triplet and Doublet were generally well-tolerated with no unexpected toxicities. The safety profiles of the BRAFTOVI Triplet and Doublet were consistent with prior reported experience with each regimen and with effects of MEK, RAF and EGFR therapies. Grade 3 or higher adverse events were seen in 58%, 50% and 61% of patients in the BRAFTOVI Triplet, Doublet and Control arms respectively. Discontinuation of therapy due to adverse events was seen in 7%, 8% and 11% of patients in the Triplet, Doublet and Control arms respectively.

On May 21, 2019, Array announced initial results from the interim analysis of the Phase 3 BEACON mCRC trial, which showed statistically significant improvement in OS and ORR with the BRAFTOVI Triplet compared to Control, reducing the risk of death by 48%.

Array intends to submit the results of the BEACON CRC trial for marketing approval in the second half of 2019.

In March 2019, the National Comprehensive Cancer Network (NCCN) updated their Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include BRAFTOVI in combination with MEKTOVI and an anti-EGFR antibody as a Category 2A treatment for patients with BRAFV600E-mutant mCRC, after failure of one or two prior lines of therapy for metastatic disease. The NCCN based their recommendation on data from the safety lead-in of the BEACON CRC trial.

The use of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAFV600E-mutant mCRC is investigational and not approved by the FDA.

A PDF of the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer presentation will be available on Array’s website at View Source

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.8 million new diagnoses in 2018. [15,16] In the U.S. alone, an estimated 140,250 patients were diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease each year. [17] BRAF mutations are estimated to occur in up to 15% of patients with mCRC and represent a poor prognosis for these patients. [1-3,12-14] The V600 mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF. [12,13] Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in BRAFV600E-mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. Benchmarks from a recent prospective Phase 2 study in a similar population include median OS of 5.9 months, median PFS of 2.0 months, and ORR of 4%. [4] BRAFV600E-mutant mCRC is an area of high unmet need as there are currently no FDA-approved therapies specifically indicated for patients with BRAF-mutant mCRC, and these patients derive limited benefit from available chemotherapy regimens. [9-11] For more information about BRAFV600E-mutant mCRC visit www.brafmcrc.com.

About BEACON CRC
BEACON CRC is a randomized, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX in patients with BRAFV600E-mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combo targeted therapy in BRAFV600E-mutant mCRC. Thirty patients were treated in the safety lead-in and received the triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and ERBITUX per label). Of the 30 patients, 29 had a BRAFV600 mutation. Microsatellite instability high, resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting initiation of the randomized portion of the trial. The randomized portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with ERBITUX with or without MEKTOVI compared to ERBITUX and irinotecan-based therapy. 665 patients were randomized 1:1:1 to receive the triplet combination, the doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). The study was amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination to the control arm. Secondary endpoints address efficacy of the doublet combination compared to the control arm, and the triplet combination compared to the doublet therapy. Other secondary endpoints include PFS, duration of response, safety and tolerability. Health related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

About BRAFTOVI + MEKTOVI
BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key enzymes in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers including melanoma, colorectal cancer, non-small cell lung cancer and others. In the U.S., BRAFTOVI + MEKTOVI are approved for the treatment of unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation, as detected by a validated test. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation. BRAFTOVI + MEKTOVI have received regulatory approval in Australia and the Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

Array has exclusive rights to BRAFTOVI and MEKTOVI in the U.S. and Canada. Array has granted Ono Pharmaceutical Co. Ltd., exclusive rights to commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize both products in all other countries, including Europe, Latin American and Asia (excluding Japan and South Korea).

Indications and Usage
BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for the treatment of patients with wild-type BRAF melanoma.

BRAFTOVI + MEKTOVI Important Safety Information
The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

Warnings and Precautions
New Primary Malignancies: Cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma, including keratoacanthoma, occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: Confirm evidence of BRAFV600E or V600Kmutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. Cardiomyopathy resolved in 87% of patients. Assess left ventricular ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. Safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal. Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform ophthalmological evaluation at regular intervals and for any visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT) and 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. Monitor liver laboratory tests before and during treatment and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum creatine phosphokinase (CPK) occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Non-hormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Adverse Reactions
The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue, nausea, diarrhea, vomiting, abdominal pain, arthralgia, myopathy, hyperkeratosis, rash, headache, constipation, visual impairment, serous retinopathy.

In the COLUMBUS trial, the most common laboratory abnormalities (≥20%, all Grades): included increased creatinine, increased CPK, increased gamma glutamyl transferase, anemia, increased ALT, hyperglycemia, increased AST, and increased alkaline phosphatase.

Drug Interactions
Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid co-administration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information. [18-19] You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Array at 1-844-Rx-Array (1-844-792-7729).

On July 5, 2019 Celyad (Euronext Brussels and Paris, and Nasdaq: CYAD), a clinical-stage biopharmaceutical company focused on the development of CAR-T cell therapies, reported that Professor Dr. Eric Van Cutsem from the University Hospital of Leuven (Universitair Ziekenhuis Leuven, UZ Leuven) presented preliminary interim data from the ongoing SHRINK and alloSHRINK Phase 1 trials assessing safety and clinical activity of the NKG2D-based CAR-T therapies CYAD-01 (autologous) and CYAD-101 (allogeneic) for the treatment of metastatic colorectal cancer (mCRC) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 21st World Congress on Gastrointestinal Cancer (WCGIC) (Press release, Celyad, JUL 5, 2019, View Source [SID1234537394]). Following the oral and poster presentations at WCGIC, Celyad’s management team will host a conference call to discuss the initial clinical results from the SHRINK and alloSHRINK trials.

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"We are encouraged by these initial results showing increased levels of cell engraftment of the non-gene edited allogeneic CAR-T candidate CYAD-101, and that following treatment with CYAD-101 we did not observe any evidence of graft versus host disease, our foremost concern with the allogeneic therapy" commented Professor Dr. Eric Van Cutsem, Gastrointestinal Oncologist at the University Hospital of Leuven. "In addition, anti-tumor activity has been observed with both the autologous CYAD-01 and allogeneic CYAD-101 candidates, in heavily pre-treated metastatic colorectal cancer patients who have received prior FOLFOX chemotherapy, providing confidence into this potential combination approach of CAR-T therapy with standard-of-care chemotherapy."

Press Release

5 July 2019

9:21 a.m. CEDT

Dr. Frédéric Lehmann, VP of Clinical Development & Medical Affairs at Celyad, commented "We are excited to share data on the first-in-class non-gene edited allogeneic CAR-T therapy CYAD-101 in metastatic colorectal cancer at ESMO (Free ESMO Whitepaper) GI in Barcelona. Professor Dr Van Cutsem gave us the great honor to share compelling clinical data for this novel class of NKG2D-based CAR-T therapies and the ability of the company’s novel T cell receptor Inhibiting Molecule, TIM, to reduce signalling of the TCR complex".

SHRINK Phase 1 Trial Update

To date, nine mCRC patients (three in each dose level (DL): DL-1: 1×108 cells, DL-2: 3×108 cells and DL-3: 1×109 cells) have been enrolled as part of the dose-escalation, SHRINK Phase 1 trial evaluating CYAD-01 administered concurrently with FOLFOX chemotherapy. Patient enrollment included four neoadjuvant first-line treatment CRC patients with resectable liver metastasis (no prior FOLFOX treatment) and five non-resectable mCRC patients with prior multiple chemotherapy lines including FOLFOX and/or FOLFIRI chemotherapy. The mean number of prior therapies received for the relapsed/refractory mCRC patients enrolled was three

Treatment with CYAD-01 with standard FOLFOX chemotherapy was generally well-tolerated, with no reports of cytokine release syndrome (CRS) grade 2 or higher, related serious adverse events (SAEs), dose-limiting toxicities (DLTs), nor on-target off-tumor toxicity

Preliminary data show a dose–dependent effect on the kinetics of cells with higher levels of cell engraftment at higher doses of CYAD-01 doses

Of the nine mCRC patients, one neoadjuvant patient experienced a partial response (PR) according to RECIST 1.1 criteria and a total of six patients experienced stable disease (SD) at month 3 including two neoadjuvant and four relapsed/refractory mCRC patients

alloSHRINK Phase 1 Trial Update

To date, a total of six patients with relapsed/refractory mCRC have been enrolled in the two first dose-levels (three each at DL-1 (1×108 cells) and DL-2 (3×108 cells)) of the alloSHRINK trial evaluating CYAD-101 administered concurrently with FOLFOX chemotherapy. The mean number of prior therapies received for the patients enrolled was four

No clinical evidence of Graft-versus-Host Disease (GvHD) have been observed. These initial data support the ability of the company’s novel inhibitory peptide TIM (T cell receptor (TCR) Inhibiting Molecule) to reduce signaling of the TCR complex

Host-versus-Graft (HvG) response against the allogeneic CYAD-101 cells appears to be controlled as evidenced by similar levels of CYAD-101 cell engraftment following the second and third infusions of the allogeneic cell therapy

At the dose levels evaluated, the treatment with CYAD-101 in association with FOLFOX chemotherapy was well-tolerated, with no reports of CRS, related SAEs, DLTs, nor on-target off-tumor toxicity

Encouraging anti-tumor activity was observed in one patient experiencing a partial response (PR) and three patients experiencing stable disease (SD) at month 3

5 July 2019

9:21 a.m. CEDT

CYAD-101 appears to provide better relative cell engraftment as compared to CYAD-01, at the same dose levels

Recruitment in DL-3 (1×109 cells) of the alloSHRINK trial is ongoing and preliminary results from the cohort are expected by year-end 2019

THINK CyFlu Phase 1 Cohort Update

Three mCRC patients were enrolled in the THINK CyFlu cohort of the Phase 1 THINK trial and received a single injection of 300 million cells of CYAD-01 following preconditioning chemotherapy of cyclophosphamide and fludarabine, or CyFlu

Treatment with CYAD-01 following CyFlu was well tolerated with no reports of CRS grade 2 or higher, related SAEs, DLTs, nor on-target off-tumor toxicity

Translational data from the cohort also suggest an improvement in cell engraftment of CYAD-01 induced by the CyFlu preconditioning as compared to the same dose of CYAD-01 without preconditioning chemotherapy

Of the three patients enrolled, one patient achieved stable disease (SD), while two patients experienced disease progression

Conference Call / Webcast Details

A conference call including a Q&A session will be held by the Company on Friday July 5, 2019 at 2:00 pm CEDT / 8:00 am EDT.

The conference call can be accessed using the details below:

United States: +1 877 407 9208

International: +1 201 493 6784

Conference ID: 13692101

Alternatively, participants may also access an audio webcast of the event using the link below: View Source

Background on CYAD-01 and CYAD-101

CYAD-01 is an investigational CAR-T therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) based on NKG2D, a receptor expressed on natural killer (NK) cells that binds to eight stress-induced ligands expressed on tumor cells. CYAD-101 is an investigational, non-gene edited, allogeneic (healthy donor derived) CAR-T therapy that co-expresses the NKG2D CAR of CYAD-01 and the novel inhibitory peptide TIM. The expression of TIM reduces signalling of the TCR complex, which is responsible for GvHD.

Press Release

5 July 2019

9:21 a.m. CEDT

Background on SHRINK and alloSHRINK Trials

SHRINK is an open-label, dose-escalation Phase 1 trial assessing the safety and activity of CYAD-01 administered concurrently with FOLFOX chemotherapy in patients with metastatic colorectal cancer (mCRC). Patients will receive six cycles of FOLFOX (combination of 5-fluorouracil, leucovorin and oxaliplatin) chemotherapy every two weeks and three administrations of CYAD-01 every two weeks.

alloSHRINK is an open-label, dose-escalation Phase 1 trial assessing the safety and clinical activity of CYAD-101 administered concurrently with FOLFOX chemotherapy in patients with unresectable mCRC. Similar to the SHRINK trial for CYAD-01, patients will receive six cycles of FOLFOX chemotherapy every two weeks and three administrations of CYAD-101 every two weeks.

Background on THINK CyFlu Cohort

In February 2018, the THINK trial was amended to include a cohort known as THINK CyFlu. The cohort evaluated a single injection of CYAD-01 following treatment with the standard preconditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), or CyFlu.

On July 5, 2019 GamaMabs Pharma, a clinical stage biotechnology company developing optimized therapeutic antibodies targeting the Anti-Müllerian Hormone Receptor II (AMHRII) for the treatment of cancer, reported the oral presentation today of clinical data from its phase 2 study of murlentamab in metastatic colorectal cancer (mCRC), at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer in Barcelona (Spain) (Press release, GamaMabs Pharma, JUL 5, 2019, View Source [SID1234537385]).

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In combination with trifluridine/tipiracil (FTD/TPI – Lonsurf), progression-free survival (PFS) was longer than expected (40% and 31% at 4 and 6 months respectively). This was especially pronounced in patients with more than 20% AMHRII-positive tumor cells, with respectively 83% and 75% patients free of progression at 4 and 6 months. 1.7-fold and 3.6-fold tumor growth rate decrease was observed with murlentamab single agent and murlentamab combined with trifluridine/tipiracil, respectively.

Immune activation under murlentamab was consistently observed in the tumor microenvironment (macrophage and T-cell activation) and in peripheral blood (monocytes and neutrophils activation). No serious adverse events related to murlentamab were reported.

Fourteen patients treated with murlentamab as a single agent (SA) and 15 patients treated in combination with FTD/TPI have been evaluated for efficacy in two parallel non-randomized cohorts.

"These first clinical and pharmacodynamic data are really encouraging for these patients who have so few options," said Professor Eric Van Cutsem, University Hospitals Leuven (Belgium), principal investigator of the study. "These results support further development of murlentamab in combination with standard chemotherapies and/or immunological agents in colorectal cancers."

"AMHRII expression was found in more than 80% of the tumor biopsied at treatment initiation in the metastatic setting, confirming our previous findings in primary tumors," said Dr. Isabelle Tabah-Fisch, Chief Medical Officer at GamaMabs Pharma. "Besides the encouraging clinical data, the pharmacodynamics changes under murlentamab confirm the rewire of the tumor microenvironment by murlentamab, from macrophage to cytotoxic T lymphocyte activation."

"Following the release in May of data on murlentamab in gynecological cancers at the ASCO (Free ASCO Whitepaper) annual meeting, presenting these phase 2 study results in mCRC at the ESMO (Free ESMO Whitepaper) World GIC congress represents another key milestone for GamaMabs," said Stéphane Degove, Chief Executive Officer at GamaMabs Pharma. "We are thrilled by the significant prolonged PFS in advanced AMHRII-medium/high mCRC patients treated by murlentamab and FTD/TPI, which encourages us to pursue the development of murlentamab in this indication with high unmet needs."

Results are being presented at the ESMO (Free ESMO Whitepaper) World Congress on Gastrointestinal Cancer on July 3-6 in Barcelona (Spain) as an oral presentation during the Emerging New or Combination Drugs in GI Cancer session on Friday, July 5, 8:00 – 9:20 a.m. (local time), and as a poster presentation.

Abstract # 214: ‘Phase 2 study results of murlentamab, a monoclonal antibody targeting the Anti-Mullerian-Hormone-Receptor II (AMHRII), acting through Tumor-Associated Macrophage engagement in advanced/metastatic colorectal cancers’ by E Van Cutsem and co-authors.

Murlentamab is a first-in-class glyco-engineered (low-fucose) monoclonal antibody selectively targeting AMHRII-expressing tumors. AMHRII, an embryonic receptor, is re-expressed in a variety of solid tumors. Murlentamab is currently being evaluated in two clinical trials, phase 1b in gynecological cancers and phase 2 in advanced or metastatic colorectal cancers. Murlentamab exerts its anti-tumor activity through tumor-associated macrophages reprogramming, resulting in enhanced tumor phagocytosis and subsequent cytotoxic T cell reactivation.

On July 5, 2019 Ipsen (Euronext: IPN; ADR: IPSEY) and Servier reported preliminary data from the Phase 1/2 study of the investigational use of liposomal irinotecan (ONIVYDE) in combination with 5- fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) in study patients with previously untreated metastatic pancreatic ductal adenocarcinoma cancer (PDAC) at the ESMO (Free ESMO Whitepaper) 21st World Congress on Gastrointestinal Cancer in Barcelona, Spain, 3–6 July 2019 (Press release, Ipsen, JUL 5, 2019, View Source [SID1234537384]). The results, which were presented as a short oral presentation, included preliminary safety and efficacy data from an ongoing multicenter, open-label, dose-escalation study, which aims to determine the maximum tolerated dose and the recommended dose to be used in future clinical studies.

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"Pancreatic cancer is aggressive and difficult to treat. With most patients going undiagnosed until the disease has spread and the prognosis is poor, some physicians may be reluctant to consider novel treatment options," said Zev Wainberg, M.D., lead investigator and associate professor of medicine, University of California Los Angeles. "It’s critical that physicians have more treatment options for their patients, particularly in the first line of therapy."

"ONIVYDE is the first and only FDA and EMA approved second-line treatment for metastatic pancreatic cancer following gemcitabine-based therapy, and the initial data presented today provides a first look into the use of this investigational therapy earlier in the treatment sequence," said Yan Moore, M.D., Ipsen’s Senior Vice President, Head of Oncology Therapeutic Area. "We look forward to further analyses of these early data, with the aim of evolving the standard of care in metastatic pancreatic cancer."

"It is vitally important to advance the research of new treatment approaches for pancreatic cancer patients, a goal Servier shares with Ipsen," said Patrick Therasse, Head of Servier Research and Development Oncology.

ONIVYDE is a topoisomerase inhibitor indicated in combination with 5-FU/LV for metastatic pancreatic cancer after disease progression following gemcitabine-based therapy. The ongoing Phase 1/2, open-label trial (NCT02551991) was designed to assess the safety, tolerability and dose-limiting toxicities (DLTs) of the study drug, liposomal irinotecan, in combination with 5-FU/LV and OX, known as NAPOX, for the first-line treatment of study participants with metastatic pancreatic cancer. Secondary objectives were to assess clinical efficacy, defined by overall response rate (ORR), disease control rate (DCR) and best overall response (BOR). Preliminary analyses of median progression-free survival and median overall survival were not mature enough for evaluation.

As of the 19 February 2019 data cut off, a total of 56 study patients (median age = 58 (39-76) years) were enrolled and dosed at 15 sites across the US, Spain and Australia. The interim analysis was conducted after all study participants in the four dose exploration cohorts had completed their second scheduled tumor evaluation at 16 weeks. Study participants from the Part 1A–cohort B (n=7) dose exploration phase and study participants from the Part 1B–dose expansion phase (n=25) received the selected dose level of liposomal irinotecan 50 mg/m2 [free-base equivalent; FBE], LV 400 mg/m2, 5-FU 2400 mg/m2, and OX 60 mg/m2. These 32 patients made up the pooled population (PP) analysis (n=29 mPDAC; n=3 locally advanced pancreatic PDAC).

Safety Results:
No reported Grade 3 or higher fatigue or peripheral neuropathy.
One study participant in the Part 1A–cohort B dose exploration phase reported a DLT (febrile neutropenia).
Treatment emergent adverse events (TEAEs) Grade 3 or higher were reported by 20 of 32 study patients in the 50/60 PP and included: neutropenia (n=9); febrile neutropenia (n=4); hypokalemia (n=4); diarrhea (n=3); nausea (n=3); anemia (n=2); vomiting (n=2).
Four study patients in the 50/60 PP reported TEAEs leading to discontinuation (n=4/32), with 23 study patients requiring dose adjustment due to AEs.
At data cut-off, 15/32 study patients in the 50/60 PP remained on treatment.
Efficacy Results:
BOR (Best Overall Response) was: one complete response (CR; study participant diagnosed with locally advanced Stage III disease), 10 partial responses (PR) in 31.3% (10/32) and 15 stable diseases (SD) in 46.9% (15/32) (sum of CR+PR+SD = 81.3%).
71.9% (23/32) of study patients in the 50/60 PP achieved disease control at 16 weeks.
Overall, 34% of study patients had a response.

ABOUT ONIVYDE (irinotecan liposome injection)
ONIVYDE is an encapsulated formulation of irinotecan available as a 43 mg/10 mL single dose vial. This liposomal form is designed to increase length of tumor exposure to both irinotecan and its active metabolite, SN-38.

Ipsen has exclusive commercialization rights for the current and potential future indications for ONIVYDE in the US. Servier is responsible for the development and commercialization of ONIVYDE outside of the U.S. and Taiwan under an exclusive licensing agreement with Ipsen.

ONIVYDE is approved by the FDA and the EMA in combination with fluorouracil (5-FU) and leucovorin (LV) for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Limitation of Use: ONIVYDE is not indicated as a single agent for the treatment of patients with metastatic adenocarcinoma of the pancreas.

IMPORTANT SAFETY INFORMATION – UNITED STATES
BOXED WARNINGS: SEVERE NEUTROPENIA and SEVERE DIARRHEA

Fatal neutropenic sepsis occurred in 0.8% of patients receiving ONIVYDE. Severe or life-threatening neutropenic fever or sepsis occurred in 3% and severe or life-threatening neutropenia occurred in 20% of patients receiving ONIVYDE in combination with 5-FU and LV.

Withhold ONIVYDE for absolute neutrophil count below 1500/mm3 or neutropenic fever. Monitor blood cell counts periodically during treatment.

Severe diarrhea occurred in 13% of patients receiving ONIVYDE in combination with 5-FU/LV. Do not administer ONIVYDE to patients with bowel obstruction. Withhold ONIVYDE for diarrhea of Grade 2–4 severity. Administer loperamide for late diarrhea of any severity. Administer atropine, if not contraindicated, for early diarrhea of any severity.

CONTRAINDICATION
ONIVYDE is contraindicated in patients who have experienced a severe hypersensitivity reaction to ONIVYDE or irinotecan HCl

Warnings and Precautions
Severe Neutropenia: See Boxed WARNING. In patients receiving ONIVYDE/5-FU/LV, the incidence of Grade 3/4 neutropenia was higher among Asian (18/33 [55%]) vs White patients (13/73 [18%]). Neutropenic fever/neutropenic sepsis was reported in 6% of Asian vs 1% of White patients

Severe Diarrhea: See Boxed WARNING. Severe and life-threatening late-onset (onset >24 hours after chemotherapy [9%]) and early-onset diarrhea (onset ≤24 hours after chemotherapy [3%], sometimes with other symptoms of cholinergic reaction) were observed

Interstitial Lung Disease (ILD): Irinotecan HCl can cause severe and fatal ILD. Withhold ONIVYDE in patients with new or progressive dyspnea, cough, and fever, pending diagnostic evaluation. Discontinue ONIVYDE in patients with a confirmed diagnosis of ILD

Severe Hypersensitivity Reactions: Irinotecan HCl can cause severe hypersensitivity reactions, including anaphylactic reactions. Permanently discontinue ONIVYDE in patients who experience a severe hypersensitivity reaction

Embryo-Fetal Toxicity: ONIVYDE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during and for 1 month after ONIVYDE treatment

Adverse Reactions
The most common adverse reactions (≥20%) were diarrhea (59%), fatigue/asthenia (56%), vomiting (52%), nausea (51%), decreased appetite (44%), stomatitis (32%), and pyrexia (23%)
The most common Grade 3/4 adverse reactions (≥10%) were diarrhea (13%), fatigue/asthenia (21%), and vomiting (11%)
Adverse reactions led to permanent discontinuation of ONIVYDE in 11% of patients receiving ONIVYDE/5- FU/LV; The most frequent adverse reactions resulting in discontinuation of ONIVYDE were diarrhea, vomiting, and sepsis
Dose reductions of ONIVYDE for adverse reactions occurred in 33% of patients receiving ONIVYDE/5 FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhea, nausea, and anemia
ONIVYDE was withheld or delayed for adverse reactions in 62% of patients receiving ONIVYDE/5-FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia
The most common laboratory abnormalities (≥20%) were anemia (97%), lymphopenia (81%), neutropenia (52%), increased ALT (51%), hypoalbuminemia (43%), thrombocytopenia (41%), hypomagnesemia (35%), hypokalemia (32%), hypocalcemia (32%), hypophosphatemia (29%), and hyponatremia (27%)
Drug Interactions
Avoid the use of strong CYP3A4 inducers, if possible, and substitute non-enzyme inducing therapies ≥2 weeks prior to initiation of ONIVYDE
Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, and discontinue strong CYP3A4 inhibitors ≥1 week prior to starting therapy
Special Populations
Pregnancy and Reproductive Potential: See WARNINGS & PRECAUTIONS. Advise males with female partners of reproductive potential to use condoms during and for 4 months after ONIVYDE treatment
Lactation: Advise nursing women not to breastfeed during and for 1 month after ONIVYDE treatment
Please see full U.S. Prescribing Information for ONIVYDE.

About the Phase 1/2 Study
The Phase 1/2, open-label, comparative trial is designed to assess the safety, tolerability and dose-limiting toxicities of irinotecan liposomal injection (ONIVYDE) in combination with 5- fluorouracil/leucovorin (5-FU/LV) and oxaliplatin (OX) as a first-line treatment for metastatic pancreatic ductal adenocarcinoma cancer patients. The study has enrolled 56 patients at 15 sites across the United States, Spain and Australia. It is being conducted in two parts:

Part 1a: a safety run-in as initial dose exploration
Part 1b: dose expansion of the nal-IRI + 5FU/LV + oxaliplatin regimen
The study’s primary endpoint is safety and tolerability. Secondary assessments of clinical efficacy include overall response rate, disease control rate and best overall response. For more information visit clinicaltrials.gov and use identifier NCT02551991.

On July 4, 2019 RhoVac AB ("RhoVac") reported positive top-line results on safety and immune response in the long-term follow-up of the Company’s phase I/II clinical trial RhoVac-001 (Press release, RhoVac, JUL 4, 2019, View Source [SID1234555928]).

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In total 22 prostatectomised cancer patients received RV001 treatment over a period of approximately 30 weeks. Following completion of treatment, all patients were monitored over a 12 months follow-up period. At 3, 6, 9 and 12 months after completion of treatment with RV001, the patients were evaluated for treatment related reactions and for immunological response. In summary, the results from the long-term follow-up evaluation can be concluded as follows:

All 22 patients recruited to the study completed the follow-up phase and during this phase no treatment related adverse events were reported.
Of the 18 patients showing significant treatment related immunological response at completion of treatment, all 18 patients still showed significant response at 3-, 6- and 9-months follow-up. At the 12-months follow-up 17 out of the 18 responding patients showed significant immunological response.
The over-all conclusion of the RhoVac-001 study including the long-term follow-up phase is that that treatment with RV001 is safe and well tolerated by prostate cancer patients. It is also concluded that a product mediated, significant, robust and long-lasting immune response is established following treatment with RV001.

Comments from RhoVac´s CEO, Anders Ljungqvist

-Receiving the results from the long-term follow-up phase of our first-in-humans clinical trial and experiencing the excellent results is fantastic. The follow-up data confirms that our product has a very good safety profile and is well tolerated by prostate cancer patients. The results also show that the immune response, which we knew was significant and robust, is also long-lasting. I don’t think anyone could have asked for better results than this and it confirms that we took the right decision, when we decided to accelerate preparation for the next clinical study. The platform for the further development of RV001 has now been completed and I am looking forward to continuing this development. Again, I must thank everyone in the company and all our collaborators outside the company for the dedicated work. A special thanks, as always, to the patients for participating in this long clinical trial. Without your commitment to the project we would never have reached this point of progress where we now are starting the phase IIb study.