MM-121 is a human IgG2 monoclonal antibody (MAb)
targeting ErbB3.
Special Report
In October 2011, several clinical trials were initiated
with MM-121 in combination with various cytotoxic drugs and
EGFr-targeted inhibitors to evaluate the effectiveness of this
anti-ErbB3 agent in the treatment of such solid tumors as ovarian, lung
and breast cancer. These trials are representative of the emerging
trend in oncology drug development that emphasizes personalized
medicine by selecting patients with a given tumor molecular profile to
be treated with targeted inhibitors addressing the putative pathway
involved in the malignancy, including alternative activators, as well
as the causes of resistance rather than inhibit one molecular moiety at
a time.
PRODUCT SOURCE
Primary Developer
Sanofi
Affiliations
Merrimack Pharmaceuticals In September 2009, Merrimack Pharmaceuticals and
Sanofi signed an exclusive worldwide licensing agreement for
the development and co-commercialization of MM-121. Under the terms of
the agreement, Sanofi will make an upfront payment of $60
million and will be responsible for all development costs. Merrimack is
eligible for an additional $470 million in milestone payments as well
as tiered double-digit royalties on sales of MM-121. Merrimack will
execute the development of MM-121 through phase II proof of concept for
each indication and Sanofi will be responsible for development
thereafter. Merrimack retains the right to co-promote the drug in the
USA.
Dyax MM-121 was identified using Dyax’s proprietary antibody
phage display library. Dyax is eligible to receive milestones
associated with the development of MM-121, as well as royalties upon
commercialization.
Funding Sources
In November 2010, Merrimack
Pharmaceuticals was granted $244,479.24 under the Qualifying
Therapeutics Discocery Project (QTDP) program for the development of
MM-121.
PRODUCT
SPECIFICATIONS
Therapeutic Indication
Malignancy
Therapeutic Category
Cytostatic • Regulation
Drug Category
Monoclonal antibody (MAb)
Drug Class
Monoclonal antibody (MAb), human
Technology
Antibody engineering • Systems
biology
Technology Details
Merrimack used a combination of high throughput biology
and computer simulation to understand the importance of targeting ErbB3
signaling in tumor cells. The company believes this is the first
systems-designed therapeutic in clinical development. Until now,
computer simulation has not been widely applied toward understanding
optimal therapeutic strategies for treating malignancies driven by
complex signaling pathways.
The fully human IgG1 MM-121 MAb to ErbB3 was identified using Dyax’s
proprietary antibody phage display library.
The sensitivity of key proteins in the network for activating pAkt were
determined among a diverse range of heterogeneous ErbB receptor
profiles. ErbB3 was an ultra-sensitive inhibition point in response to
either betacellulin or heregulin. This was verified by developing and
testing a novel anti-ErbB3 antibody, MM-121, in cell based assays.
MM-121 was also more effective at inhibiting heregulin-induced pErbB3
and pAkt than other agents targeting the ErbB pathway further
supporting the findings. The kinetic parameters of MM-121 were also
used to build an in silico version of the inhibitor that was used to
predict the IC50 values of pAkt and pErbB3 in response to MM-121 in a
number of cell lines stimulated with heregulin or betacellulin. These
predictions were experimentally verified. In vitro findings were
further validated in vivo using multiple xenograft models. Human IgG2
monoclonal antibodies against ErbB3 were then developed and tested in
multiple orthogonal assays for their ability to modulate ErbB3 activity
and one candidate, MM-121, was chosen to move forward into preclinical
testing (Schoeber BM, etal, AACR08, Abs. 1638).
Mechanism
Signal transduction modulation
Mechanism Details
MM-121 is designed to block signaling of the ErbB3
belonging to the ErbB family of receptors, a pathway that plays a
critical role in cancer signaling. A central theme of acquired
resistance is persistent ErbB3 signaling, resulting in activation of
the PI3K/AKT survival pathway. ErbB3 is recognized as a potentially
important target in many types of malignancies including lung, breast,
colorectal, and ovarian cancer, among others. In preclinical studies,
MM-121 demonstrated antitumor activity in a wide range of tumor types
and a very favorable safety profile.
MM-121 potently inhibits heregulin-induced signaling events in human
cancer cell lines and, in dose-dependent manner, and tumor growth in
multiple xenograft models of human cancer, including ovarian, kidney,
pancreatic and prostate cancer. According to pharmacodynamic analysis
of samples from preclinical studies, chronic MM-121 administration
results in inhibition of ErbB3 activity which correlated with efficacy.
Cumulatively, these data supported that MM-121 may offer significant
clinical benefits in the treatment of cancer. Using Merrimack
Pharmaceutical’s Network Biology platform, investigators identified
potentially beneficial drug combinations of MM-121 with other ErbB
inhibition therapies, such as cetuximab, lapatinib, and PI3K
inhibitors. These simulations predicted optimal drug combinations for
the inhibition of pErbB3 and pAKT in a wide range of cancer cell lines.
Based on these simulations, the pErbB3 and pAKT levels were measured in
a subset of cancer cell lines treated with these combinations which
were also tested on their effect on cell growth. Based on the in vitro
results and the model simulations, these drug were tested in xenograft
mouse models of cancer (Onsum M, etal, AACR09, Abs. 3244).
MM-121 demonstrated potent inhibition of heregulin-induced signaling
events in human cancer cell lines. When MM-121 efficacy was assessed in
vivo, MM-121 inhibited tumor growth in a dose-dependent manner in
multiple xenograft models of human malignancies, including ovarian,
renal cell, pancreatic and prostate cancer. According to
pharmacodynamic analysis of samples from these studies, chronic MM-121
administration resulted in inhibition of ErbB3 activity, which
correlated with efficacy. In vitro antibody binding studies suggest
that MM-121 binds to ErbB3 receptors from mouse, rat, cynomolgus monkey
and human with a similar affinity. In order to design an efficacious
and safe dosing regimen, preclinical studies were carried out in mouse,
rat and cynomolgus monkey. These studies suggest that MM-121 can safely
be administered at serum levels that result in favorable inhibition of
ErbB signaling and efficacy in xenograft models of cancer (Schoeber BM,
etal, AACR08, Abs. 3974).
Target
HEr3, ErbB3, ErbB-3
Administration Route
intravenous (IV)
Diagnostic Test/Biomarker Detail
Investigators at Merrimack Pharmaceuticals developed a
preclinical classifier to predict xenograft response to MM-121, based
on the measurement of a few key biomarkers in cell lysates. The 5 most
critical proteins for predicting activation of phospho-AKT, including
ErbB3 and its ligand heregulin, were identified using a computational
model of the ErbB signaling pathway. These biomarkers were profiled in
a large panel of cancer cell lines, and in 8 xenograft tumor models. A
classification rule for predicting xenograft response was then
determined using the measured effect of MM-121 on inhibiting tumor
growth and was subsequently used to correctly predict a priori MM-121
response in 11 xenograft models. These results suggest that this
computationally derived biomarker signature is sufficient for
predicting response to MM-121 in xenografts, and could offer
significant clinical benefit by helping select patients for MM-121
(Xiao D, etal, ASCOMM10, Abs. 1033)
Cancer Indication
solid tumor • breast cancer •
colorectal cancer • lung cancer • ovarian cancer
CLINICAL
STATUS BY INDICATION
Indication
solid tumors, advanced,
refractory
Latest Status
Phase I (begin 7/08, ongoing
1/11) USA, phase I (begin 10/11) USA (combination), phase I (begin
10/11) USA (combination)
Clinical History
A nonrandomized, open label, phase I clinical trial
(protocol ID: MM-121-06-01-06 (TCD11694); NCT01447225;
http://clinicaltrials.gov/ct2/show/NCT01447225 ) was initiated in
October 2011, in the USA, to evaluate the safety of MM-121 in
combination with gemcitabine, carboplatin, or pemetrexed in treating
patients with advanced solid tumors. The trial’s primary objective is
to determine the number of DLT. According to the protocol, the dose
escalation portion of the trial employs a 3 + 3 design to assess the
safety, tolerability, and PK of MM-121 administered weekly in
combination with certain anticancer therapies in patients with advanced
or recurrent cancer. Doses of IV MM-121 are escalated when administered
in combination with a fixed dose of gemcitabine, carboplatin, or
pemetrexed until either the MTD is identified or the combination is
shown to be tolerable at the highest planned doses. The trial is to
enroll about 36 patients.
A multicenter (n=4), nonrandomized, open label, does escalation, phase
I clinical trial (protocol ID: MM-121-05-01-05 (TCD11696); NCT01451632;
http://clinicaltrials.gov/ct2/show/NCT01451632 ) was initiated in
October 2011, in the USA, to evaluate the safety of MM-121 in
combination with cetuximab and irinotecan in treating patients with
advanced malignancies. The trial’s primary objective is to determine
the number of DLT. According to the protocol, patients are administered
escalating doses of MM-121 in combination with cetuximab plus
irinotecan. The trial is to enroll about 45 patients.
A nonrandomized, open label, dose escalation, phase Ib clinical trial
(protocol ID: TCD11721; U1111-1121-4146; NCT01436565;
http://clinicaltrials.gov/ct2/show/NCT01436565 ) was initiated in
September 2011, to evaluate the safety of SAR245408 in combination with
SAR256212 in treating patients with metastatic or locally advanced
nonhematologic cancer, for which no alternative therapy is available.
The trial’s primary objective is to determine the MTD. Secondary
objectives are to evaluate the peak and through levels, pharmacodynamic
change, number of patients with AE, ORR, and the number of patients who
develop anti-MM-121 antibodies. According to the protocol, patients are
administered oral SAR245408 every morning (no eating 2 hours prior and
1 hour after dose) in combination with SAR256212 IV infusion weekly
over 1 hour, right after the SAR245408 dose. There is a 28-day
screening period followed by a 28-day treatment cycle (21-day cycle for
every 3-week dosing regimen, if used). Patients will continue treatment
as long as there is clinical benefit or until a trial withdrawal
criterion is met. The last post-treatment visit is 60 days after the
lase dose or until toxicity. The trial, to enroll about 56 patients,
had not opened for recruitment as of September 2011.
In August 2008, the first patient was treated in a dose-escalation
phase I clinical trial with MM-121, a first-in-class therapeutic
designed to block signaling of the ErbB3 receptor. MM-121 becomes the
first systems biology product as well as the first selective ErbB3
antagonist to enter human clinical development. The phase I clinical
trial will evaluate the safety and PK of MM-121.
A multicenter (n-3), open label, dose-escalation phase I clinical trial
(protocol ID: MM-121-01-100, MM-121; NCT00734305;
http://clinicaltrials.gov/ct2/results?term=NCT00734305 ) was initiated
in the USA, in July 2008, in patients with refractory advanced solid
tumors. Using a ‘3+3’ design, successive cohorts of 3 or more patients
are treated at escalating doses until a MTD is identified. The trial
will initially explore an every 7-day a dosing schedule, which may be
modified to longer intervals under certain circumstances. Once MTD or
the recommended phase II dose is identified, an expansion cohort will
be enrolled at that dose to further characterize safety and to explore
pharmacodynamic endpoints. The trial’s primary objectives are to
determine the phase II dose based either on the MTD or maximum feasible
dose in patients with advanced solid tumors, and any objective response
to MM-121 based on RECIST. Secondary objectives are to identify DLT,
determine the drug’s AE and its PK profile, and describe certain
pharmacodynamic parameters. Estimated enrollment is 40 patients.
Participating centers include Fox Chase Cancer Center, under PI Crystal
Denlinger, MD; Dana-Farber Cancer Institute, under PI Kwok Kin Wong,
MD; and Vanderbilt-Ingram Cancer Center, under PI Mace Rothenberg, MD.
Indication
non-small cell lung cancer
(nsclc), locally advanced or metastatic
Latest Status
Phase I/II (begin 2/10, ongoing
7/11) USA (combination)
Clinical History
The phase I/II clinical trial (protocol ID:
MM-121-01-101; NCT00994123) is evaluating three distinct groups of
patients with non-small cell lung cancer (nsclc) treated with MM-121 in
combination with erlotinib. The rationale of the scheme stems from the
fact that although EGRr inhibitors such as erlotinib are very effective
at first in treating EGFr-addicted malignancies, resistance often
hampers their long term outlook. This phenomenon may be the result of
tumor cells becoming resistant to EGFr inhibitors by the upregulation
of survival signaling via ErbB3-dependent activation of the PI3K/AKT
pathway. In preclinical studies, simultaneous inhibition of EGFr and
ErbB3 produces an additive effect on tumor growth inhibition in nsclc.
This trial is evaluating the role of MM-121 as an ErbB3 inhibitor in 3
patient groups, EGFR-TKI naïve patients with wt EGFr previously
treated with at least 1 line of chemotherapy to assess whether MM-121
enhances intrinsic sensitivity of tumors to erlotinib (group A);
EGFr-TKI naïve patients with mutated EGFr to assess whether MM-121
delays or prevents acquired resistance or enhances intrinsic
sensitivity to erlotinib (Group B); and patients with mutated EGFr
previously responding to single agent EGFR TKI but subsequently
developing acquired resistance, to assess whether MM-121 can reverse
acquired resistance. The phase I portion of the trial is evaluating
safety at escalating doses of the combination, as well as varying
dosing schedules of the combination. The primary endpoint of the phase
II portion is PFS in each group. Secondary endpoints include OS and ORR
of the combination. In addition, the trial is evaluating AE, PK,
immunogenicity and biomarker profiles (Sequist LV, etal, ASCO11, Abs.
TPS215). Participating institutions include Massachusetts General
Hospital Cancer Center (Boston, MA), Horizon Oncology Center
(Lafayette, IN), Arizona Clinical Research Center (Tucson, AZ), and
Dana-Farber Cancer Institute (Boston, MA). The trial enrolled 7 cohorts
to evaluate varying dose levels of the combination, as well as
alternate MM-121 infusion schedules. Dose levels were determined by
safety and PK data. Among the 33 patients enrolled between February
2010 and July 2011, 24 patients were erlotinib-naïve and in 1
patient the tumor harbored an EGFr mutatation. In this trial, MM-121
plus erlotinib was well tolerated by the majority of patients (Sequist
LV, etal, AACR-NCI-EORTC11, Abs. C27).
The first patient was dosed in November 2011 in the phase II portion of
the phase I/II clinical trial (protocol ID: MM-121-01-101; NCT00994123)
with MM-121 in combination with erlotinib (Tarceva) to estimate PFS in
three distinct patient populations with metastatic nsclc. Group A
includes patients with tumors without EGFr activating mutations that
progressed or recurred following at least one chemotherapy-containing
regimen excluding prior EGFr targeted therapy. These patients are
randomized to either MM-121 in combination with erlotinib or erlotinib
alone. Group B includes patients with tumors expressing an EGFR
activating mutation who have not been previously treated with an EGFr
targeted therapy. These patients are randomized to either MM-121 in
combination with erlotinib or erlotinib alone. Fnally, Group C includes
patients with tumors that responded to EGFr targeted therapy and have
subsequently acquired resistance. These patients will be treated with
MM-121 in combination with erlotinib. The trial is being conducted at
multiple sites in North America, Europe and Asia. The trial is designed
to enroll approximately 229 patients across all three arms. The first
patient was enrolled at the Loma Linda University Cancer Center.
A nonrandomized, open label, dose-escalation phase I/II clinical trial
(protocol ID: MM-121-01-101; NCT00994123;
http://clinicaltrials.gov/ct2/results?term=NCT00994123 ) was initiated
in February 2010, in the USA, at the Horizon Oncology Center
(Lafayette, IN), to evaluate the safety and efficacy of MM-121 in
combination with erlotinib in treating patients with locally advanced
or metastatic non-small cell lung cancer (nsclc) who had not been
treated with prior anti-EGFr or anti-ErbB3 regimens. The trial’s
primary objective is to establish the recommended phase II dose. A
secondary objective is to estimate the non-PR rate at >/=24 weeks.
According to the protocol, during phase I, in the dose escalation
cohorts, patients are administered MM-121 IV weekly and erlotinib
daily. During phase II, patients are treated with IV MM-121 weekly and
erlotinib is administered daily. Treatment is administered at the MTD
or maximum feasible dose identified in phase I. The trial is to enroll
about 40 patients.
Indication
breast cancer, postmenopausal,
locally advanced or metastatic, hormone receptor positive, HEr2
negative, second line
Latest Status
Phase II (begin 7/10, ongoing
3/11) USA
Clinical History
In the double blind, randomized phase II clinical trial
(protocol ID: MM-121-02-02-03; NCT01151046) with exemestane with or
without MM-121, depending on the treatment assignment, MM-121 or
placebo is administered as a 60 minute IV infusion once weekly and
exemestane (25 mg) orally once daily. The trial is designed to
demonstrate whether the combination of MM-121 plus exemestane is more
effective than exemestane alone in patients with Er+ and/or PR+ and
HEr2-negative breast cancer refractory to prior anti-estrogen therapy
in the locally advanced or metastatic setting. Patients are treated
until radiologic or clinical disease progression is documented. The
trial is to enroll 130 patients, from multiple sites globally, to be
randomized in a 1:1 ratio to either MM-121 plus exemestane, or placebo
plus exemestane. The trial’s primary objective is to determine whether
the combination of MM-121 plus exemestane is more effective than
exemestane monotherapy based on PFS. Secondary objectives include OS,
ORR and CBR (Moyo VM, etal, ASCO11, Abs. TPS112), Participating
institutions include Massachusetts General Hospital (Boston, MA),
Pasco-Pinellas Oncology (New Port Richey, FL), Hematology Oncology
Associates of the Treasure Coast (Port St. Lucie, FL) and Pacific
Cancer Medical Center (Anaheim, CA).
A mulitcenter (n=5), randomized, double blind, placebo control, phase
II clinical trial (protocol ID: MM-121-02-02-03; NCT01151046;
http://clinicaltrials.gov/ct2/show/NCT01151046 ) was initiated in June
2010, in the USA, to evaluate the safety and efficacy of exemestane
with or without MM121 in treating postmenopausal women with locally
advanced or metastatic, Er positive, Pr positive, and HEr2 negative
breast cancer refractory to first line anti-estrogen therapy and that
progressed during (or within 6 months of completing) adjuvant therapy
with a non-steroidal aromatase inhibitor and/or tamoxifen. The trial’s
primary objective is to determine the efficacy based on PFS. According
to the protocol, patients are administered either MM-121 or placebo (40
mg/kg loading dose week 1, then 20 mg/kg) by IV infusion over 60
minutes once per week in combination with exemestane (25 mg) orally
once per day. The trial is to enroll about 130 patients.
Indication
breast cancer, locally advanced
or metastatic, HEr2 negative • ovarian cancer, locally advanced or
metastatic or recurrent • endometrial cancer, ocally advanced or
metastatic or recurrent
Latest Status
Phase I (begin 10/10, ongoing
1/11) USA (combination
Clinical History
A multicenter (n=3), open label, phase I clinical trial
(protocol ID: MM-121-04-01-04; NCT01209195;
http://clinicaltrials.gov/ct2/show/NCT01209195 ) was initiated in
October 2010, in the USA, at Pinnacle Oncology Hematology (Scottsdale,
AZ), Comprehensive Blood and Cancer Center (Bakersfield, CA), and at
Dana-Farber Cancer Institute (Boston, MA), to evaluate the safety of
MM-121 in combination with paclitaxel in treating patients with locally
advanced, metastatic or recurrent epithelial ovarian, fallopian tube,
primary peritoneal, or endometrial cancer or patients with locally
advanced or metastatic, HEr2-negative breast cancer. Patients must be
candidates for chemotherapy. The trial’s primary objective is to assess
the number and severity of AE. Secondary objectives are to evaluate
efficacy, PK, and to determine whether MM-121 in combination with
paclitaxel elicits an immune response. According to the protocol,
patients in cohort 1 are administered MM-121 (20 mg/kg) loading dose
followed by MM-121 (12 mg/kg) IV infusion weekly. Patients are then
administered paclitaxel (80 mg/m²) IV infusion weekly. Patients in
cohort 2 are administered a loading dose of MM-121 (40 mg/kg) followed
by MM-121 (20 mg/kg) IV infusion weekly. Patients are administered
paclitaxel as in cohort 1. Intermediate doses between cohort 1 and 2
may also be considered. The trial is to enroll about 24 patients.
Indication
breast cancer, nonmetastatic, Er
positive, HEr2 negative, neoadjuvant • breast cancer, nonmetastatic,
triple negative, neoadjuvant
Latest Status
Phase II (begin 8/11) USA
(combination)
Clinical History
A multicenter (n=21), randomized, open label, phase II
clinical trial (protocol ID: MM-121-02-02-07 (ARD11918); NCT01421472;
http://clinicaltrials.gov/ct2/show/NCT01421472 ) was initiated in
August 2011, in the USA, to evaluate the efficacy of MM-121 in
combination with paclitaxel in treating treatment-naïve patients
with non-metastatic HEr2-negative, Er-positive breast cancer or triple
negative breast cancer in the neoadjuvant setting. The trial’s primary
objective is to determine the pathologic CR rate. According to the
protocol, patients are randomized to paclitaxel with or without MM-121
for 12 weeks followed by 4 cycles of doxorubicin plus cyclophosphamide
and subsequent surgery. Patients may also be randomized to be treated
with paclitaxel IV followed by standard dosing of doxorubicin IV plus
cyclophosphamide IV, followed by surgery. The trial is to enroll about
200 patients.
Indication
ovarian cancer, epithelial,
platinum-resistant or refractory • fallopian tube cancer,
platinum-resistant or refractory • peritoneal cancer, primary,
platinum-resistant or refractory
Latest Status
Phase II (begin 10/11) USA
(combination)
Clinical History
A randomized, open label, phase II clinical trial
(protocol ID: MM-121-04-02-08 (ARD11586); NCT01447706;
http://clinicaltrials.gov/ct2/show/NCT01447706 ) was initiated in
October 2011, in the USA, at the Comprehensive Blood and Cancer Center
(Bakersfield, CA), to evaluate the efficacy of MM-121 in combination
with paclitaxel versus paclitaxel alone in treating patients with
platinum resistant or refractory, advanced epithelial ovarian,
fallopian tube, or primary peritoneal cancer previously treated with a
at least one platinum chemotherapy regimen. The trial’s primary
objective is to determine PFS. According to the protocol, patients are
randomized (2:1) to be administered paclitaxel alone or in combination
with MM-121. The trial is to enroll about 210 patients.
