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A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C

October 2017
Investigational New Drugs 35(4)

Authors:

Background This phase II open-label, multicenter study evaluated the efficacy, safety, and tolerability of TAK-264 in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). Methods Patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC (H-score ≥ 10) received TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min intravenous infusion for up to 1 year or until disease progression or unacceptable toxicity. The primary objective was overall response rate (ORR [complete response + partial response (PR)]). Secondary objectives included evaluations of the safety and pharmacokinetic profile of TAK-264 (NCT02202785). Results 43 patients were enrolled and treated with 1.8 mg/kg TAK-264: 11, 15, and 17 patients with low, intermediate, and high GCC expression, respectively. Median number of treatment cycles received was two (range 1-10). The ORR was 3%, including one patient with intermediate GCC expression who achieved a PR. All patients experienced ≥1 adverse events (AE). The majority of patients experienced grade 1/2 AEs affecting the gastrointestinal tract. Fifteen (35%) patients experienced ≥grade 3 drug-related AEs; five (12%) patients had a serious AE. The most common (≥10% of patients) all-grade drug-related AEs were nausea (33%), fatigue (28%), neutropenia (23%), decreased appetite (23%), vomiting (16%), asthenia (16%), and alopecia (14%). Conclusions TAK-264 demonstrated a manageable safety profile; however, the low efficacy of TAK-264 observed in this study did not support further clinical investigation.

Study overview. *Response-evaluable patients. GCC: guanylyl cyclase C

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PHASE II STUDIES

A phase II study of antibody-drug conjugate, TAK-264

(MLN0264) in previously treated patients with advanced

or metastatic pancreatic adenocarcinoma expressing

guanylyl cyclase C

Khaldoun Almhanna

&David Wright

&Teresa Macarulla Mercade

Jean-Luc Van Laethem

&Antonio Cubillo Gracian

5,6

&Carmen Guillen-Ponce

Jason Faris

&Carolina Muriel Lopez

&Richard A. Hubner

&Johanna Bendell

Alain Bols

&Jaime Feliu

&Naureen Starling

&Peter Enzinger

Devalingham Mahalingham

&Wells M es se rsmith

&Huyuan Yang

Adedigbo Fasanmade

&Hadi Danaee

&Thea Kalebic

Received: 2 May 2017 /Accepted: 10 May 2017 /Published online: 19 May 2017

#Springer Science+Business Media New York 2017

Summary Background This phase II open-label, multicenter

study evaluated the efficacy, safety, and tolerability of TAK-

264 in previously treated patients with advanced or metastatic

pancreatic adenocarcinoma expressing guanylyl cyclase C

(GCC). Methods Patients with advanced or metastatic pancre-

atic adenocarcinoma expressing GCC (H-score ≥10) received

TAK-264 1.8 mg/kg on day 1 of a 21-day cycle as a 30-min

intravenous infusion for up to 1 year or until disease progres-

sion or unacceptable toxicity. The primary objective was over-

all response rate (ORR [complete response + partial response

(PR)]). Secondary objectives included evaluations of the safe-

ty and pharmacokinetic profile of TAK-264 (NCT02202785).

Results 43 patients were enrolled and treated with 1.8 mg/kg

TAK-264: 11, 15, and 17 patients with low, intermediate, and

high GCC expression, respectively. Median number of treat-

ment cycles received was two (range 1–10). The ORR was

3%, including one patient with intermediate GCC expression

who achieved a PR. All patients experienced ≥1adverse

events (AE). The majority of patients experienced grade 1/2

AEs affecting the gastrointestinal tract. Fifteen (35%)patients

experienced ≥grade 3 drug-related AEs; five (12%)patients

had a serious AE. The most common (≥10%of patients) all-

grade drug-related AEs were nausea (33%), fatigue (28%),

neutropenia (23%), decreased appetite (23%), vomiting

*Khaldoun Almhanna

Khaldoun.Almhanna@moffitt.org

Department of Gastrointestinal Oncology, Moffitt Cancer Center,

12902 Magnolia Drive, Tampa, FL 33612, USA

Florida Cancer Specialists, Tampa, FL, USA

Vall d’Hebron University Hospital, Barcelona, Spain

Erasme University Hospital, Brussels, Belgium

HM Universitario Sanchinarro, Centro Integral Oncológico Clara

Campal (CIOCC), Madrid, Spain

Departamento de Ciencias Médicas Clínicas, Universidad San Pablo

CEU, Madrid, Spain

Ramón y Cajal University Hospital, Madrid, Spain

Massachusetts General Hospital Cancer Center, Boston, MA, USA

Hospital Universitario Virgen de la Victoria, Málaga, Spain

The Christie NHS Foundation Trust, Manchester, UK

Sarah Cannon Research Institute/Tennessee Oncology,

Nashville, TN, USA

Brugge Oostende Oncologisch Centrum, Bruges, Belgium

CIBERONC, La Paz University Hospital, Madrid, Spain

The Royal Marsden NHS Foundation Trust, London, UK

Dana Farber Cancer Institute, Boston, MA, USA

University of Texas Health Science Center, San Antonio, TX, USA

University of Colorado, Aurora, CO, USA

Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of

Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

Invest New Drugs (2017) 35:634–641

DOI 10.1007/s10637-017-0473-9

Content courtesy of Springer Nature, terms of use apply. Rights reserved.

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NEW ENGL J MED

Background In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. Methods We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. ResultsA total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. Conclusions In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.) In this report, the addition of nab-paclitaxel to standard gemcitabine increased the response rate, progression-free survival, and overall survival among patients with metastatic pancreatic adenocarcinoma. Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States.(1),(2) Since 1997, gemcitabine therapy has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer.(3) Among patients with metastatic disease, the 5-year survival rate is only 2%,(1) and 1-year survival rates of 17 to 23% have been reported with gemcitabine.(3)-(5) Numerous phase 2 studies involving patients with advanced pancreatic cancer have shown promising results; however, most subsequent large phase 3 studies have not shown significantly improved survival,(6)-(16) with the exception of a study involving patients who ...

Guanylyl Cyclase C as a Biomarker in Colorectal Cancer

Article

Full-text available

Feb 2013
BIOMARK MED

While histologic assessment of nodes is a component of all colon cancer staging paradigms, approximately 30% of patients with histology-negative nodes (pN0) die of disseminated disease reflected by occult nodal metastases. Undetected metastases are particularly important when considering racial disparities in colon cancer, where black subjects with pN0 disease exhibit the greatest differences in outcomes, with >40% excess mortality. Recently, guanylyl cyclase C (GCC), a protein normally restricted to intestinal cells, but universally expressed by colorectal cancer cells, was validated for detecting occult metastases. Indeed, occult tumor burden across regional lymph nodes estimated by GCC quantitative reverse transcription PCR identifies pN0 patients with near zero risk, and those with >80% risk, of unfavorable outcomes. Disproportionately high occult tumor burden in black patients underlies racial disparities in stage-specific mortality. These studies position the platform encompassing quantification of occult tumor burden by GCC quantitative reverse transcription PCR for translation, as a detect-treat paradigm to reduce racial disparities in colon cancer mortality.

GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC cancer base no. 11 [Internet]. International Agency for Research on Cancer, Lyon

Article

Jan 2014

Abstract PR12: MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC), demonstrates antitumor activity alone and in combination with gemcitabine in human pancreatic cancer xenograft models expressing GCC

Article

Jan 2014

Background: MLN0264 consists of a fully human anti-GCC monoclonal antibody linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker (MMAE and linker technology licensed from Seattle Genetics). The transmembrane cell surface receptor GCC is expressed by ∼95% of primary and metastatic colorectal cancer (mCRC) tumors. MLN0264 has shown selective binding and antitumor activity in mouse xenograft models of mCRC expressing GCC, and is currently being investigated in a phase 1 study in patients with advanced gastrointestinal malignancies. GCC is also expressed in subsets of pancreatic cancers. Further to the findings in mCRC, we investigated GCC expression in human pancreatic tumors and evaluated MLN0264 activity in mouse xenograft models of GCC-expressing human pancreatic cancer. Methods: GCC expression in multiple human pancreatic cancer samples including tissue microarrays (TMAs) was evaluated by immunohistochemistry (IHC). For in vivo studies, 7 mouse xenograft primary human tumor explant (PHTX) models of pancreatic cancer were developed, including tumor tissue from patients with wild-type and mutant KRAS. Animals were treated when the tumor reached ∼230 mm3. In single-agent studies, animals were administered vehicle, MMAE 0.135 mg/kg once weekly (QW), or MLN0264 3.75 or 7.5 mg/kg QW. In combination studies, animals received vehicle, or MLN0264 7.5 mg/kg QW alone or in combination with gemcitabine 15 or 20 mg/kg twice weekly (BIW), or gemcitabine 15 mg/kg on days 1, 3 each week. Average tumor volume was determined at multiple time points following the start of treatment using vernier callipers. Results: In the GCC-expressing PHTX-249 mouse xenograft model (KRAS mutant G12), single-agent MLN0264 showed significant tumor growth inhibition (TGI) versus vehicle or free MMAE by day 21, with the 7.5 mg/kg dose significantly better than 3.75 mg/kg by day 20-22. Similarly, in the GCC-expressing PHTX-215 model (KRAS wild-type), MLN0264 7.5 mg/kg resulted in significantly greater TGI (79%) versus free MMAE or MLN0264 3.75 mg/kg by day 22, including some tumor regression. Across the 7 models (variable apical GCC expression; KRAS wild-type and mutant), TGI ranged from 24% (p=0.17) to 79% (p<0.001) with single-agent MLN0264. In the PHTX-249 model, MLN0264 7.5 mg/kg plus gemcitabine 15/20 mg/kg BIW or 15 mg/kg, days 1, 3, showed significantly greater TGI than either agent alone. At day 20-21, TGI was 46-47% for single-agent MLN0264, 66-79% for gemcitabine 15 mg/kg BIW and gemcitabine days 1, 3, and 84-88% for the respective combinations; 3 of 7 animals in the latter combination group had a smaller tumor volume at day 20 versus day 0 (TGI, 93%). Conclusions: These findings indicate that MLN0264 has antitumor activity as a single agent and in combination with gemcitabine in GCC-expressing pancreatic cancer xenograft models, and support clinical evaluation of MLN0264 in patients with pancreatic cancer. Data from additional models will be presented. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR12. Citation Format: Julie Zhang, Melissa Gallery, Tim Wyant, Brad Stringer, Mark Manfredi, Hadi Danaee, Petter Veiby. MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC), demonstrates antitumor activity alone and in combination with gemcitabine in human pancreatic cancer xenograft models expressing GCC. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR12.

Antibody-drug conjugates: Current status and future directions

Article

Nov 2013

Antibody-drug conjugates (ADCs) aim to take advantage of the specificity of monoclonal antibodies (mAbs) to deliver potent cytotoxic drugs selectively to antigen-expressing tumor cells. Despite the simple concept, various parameters must be considered when designing optimal ADCs, such as selection of the appropriate antigen target and conjugation method. Each component of the ADC (the antibody, linker and drug) must also be optimized to realize fully the goal of a targeted therapy with improved efficacy and tolerability. Advancements over the past several decades have led to a new generation of ADCs comprising non-immunogenic mAbs, linkers with balanced stability and highly potent cytotoxic agents. Although challenges remain, recent clinical success has generated intense interest in this therapeutic class.

A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C

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