Conditions: Leukemia
Keywords: Leukemia Hematological malignancy Myelofibrosis MF Blastic plasmacytoid dendritic cell neoplasm BPDCN CD56 tumor marker Acute myeloid leukemia AML Natural-killer leukemia Acute lymphoblastic leukemia ALL CD56 expressing hematological malignancy IMGN901 Lorvotuzumab mertansine
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The goal of this clinical research study is to learn if lorvotuzumab mertansine can help to control blood cancers that have the CD56 tumor marker. The safety of this drug will also be studied.

Detailed description:
Study Treatment:

If you are found to be eligible to take part in this study, you will receive lorvotuzumab by vein on Days 1 and 8 (+/- 2 days) of each cycle. It may take a few minutes or several hours to receive the study drug. Your doctor will discuss this with you.

All treatments with IMGN901 must be administered at MD Anderson.

Each cycle is 21 days (+/-6 days). However, they may be longer or shorter depending on if/how the disease responds to the treatment, how your bone marrow reacts to treatment, and what the doctor thinks is in your best interest.

Your dose of lorvotuzumab may be raised, lowered, and/or delayed if the doctor thinks it is in your best interest.

Study Visits:

On Day 1 of each cycle, you will have a physical exam.

One (1) time each week during the first 4 cycles, blood (about 1 tablespoon) will be drawn for routine tests. After Cycle 4, you will have these blood draws 1 time every 2-4 weeks. If your doctor thinks it is needed, more blood may need to be drawn. The study doctor or study staff will discuss this with you if more blood is needed.

During the first cycle, all the laboratory evaluations will be done at MD Anderson. After Cycle 1, you may be able to have these blood draws performed at a local lab or clinic that is closer to your home, and the results reported to the research nurse of the study at MD Anderson. The study doctor or study staff will discuss this option with you. The results of these blood draws will be sent to the study doctor for review.

On Day 21 of Cycle 1 (+/- 7 days), then every 1-3 cycles after that, you will have a bone marrow aspiration/biopsy to check the status of the disease. If the doctor thinks it is needed, these may be done more or less often, depending on your response to the study drug.

You will have blood draws and/or bone marrow aspirations at any time that the doctor thinks it is needed while you are on study.

If you stay on study for more than 6 months and you are not having side effects, you may have some of the above tests more or less frequently. For example, you may only have a bone marrow aspiration 1 time every 6-12 months and blood draws 1 time each cycle. The study doctor will discuss this with you.

Length of Study:

You may take up to 12 cycles of lorvotuzumab. If the doctor thinks it is in your best interest, you may be able to continue receiving the study drug beyond Cycle 12. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after follow-up.

End-of-Study Visit:

If you leave the study before the end of Cycle 12, within 30 days (+/- 7 days) after the last dose of study drug:

* Blood (about 2-3 tablespoons) will be drawn for routine tests.
* If the doctor thinks it is needed, you will have a bone marrow aspirate/biopsy to check the status of the disease.

Long Term Follow-Up:

If the disease appears to get better and you are responding well to the study drug, you will return to MD Anderson every 3-6 months for up to 5 years after your last dose of study drug for the study staff to check how you are doing.

If you cannot return to MD Anderson for these visits, you may be called by a member of the study staff. The call should last about 10 minutes.

This is an investigational study. Lorvotuzumab is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the drug is designed to work.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Arms:
arm 1: Lorvotuzumab mertansine (IMGN901) administered intravenously at a dose of 100 mg/m2 on Day 1 and 8 of a 21-day cycle. arm 2: Lorvotuzumab mertansine (IMGN901) administered intravenously at a dose of 100 mg/m2 on Day 1 and 8 of a 21-day cycle. arm 3: Lorvotuzumab mertansine (IMGN901) administered intravenously at a dose of 100 mg/m2 on Day 1 and 8 of a 21-day cycle.

Interventions: intervention 1: Lorvotuzumab Mertansine (IMGN901)
Intervention descriptions: intervention 1: 100 mg/m2 by vein on Day 1 and 8 of a 21-day cycle.

Protocol document:
Prot_000.pdf: 
IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
1
 
 
 
An Open-label Phase II Study of Lorvotuzumab mertansine (IMGN901) in CD56 
expressing hematological malignancies 
 
 
 
Principal Investigator: Naval Daver, M.D. and Hagop Kantarjian, M.D. 
  
 
Sponsor: IND office, University of Texas, MD Anderson Cancer Center 
 
 
IND number: 125,990. 
Protocol number: 2014-0926 
 
 
University of Texas  
 
MD Anderson Cancer Center  
 
Leukemia Department, Unit 428  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 OBJECTIVES 
 
1.1 Primary Objectives  
    
1. To determine the overall response rate of IMGN901 in CD56 expressing 
hematological malignancies including but not limited to relapsed/refractory 
acute leukemias, myelofibrosis (MF) refractory to JAK-inhibitor therapy and 
blastic plasmacytoid dendritic cell neoplasm (BPDCN).  
1.2 Secondary Objectives 
 
1. To determine the duration of response, event-free survival (EFS), and overall 
survival (OS) in patients to IMGN901 in CD56 expressing hematological 
malignancies including but not limited to relapsed/refractory acute leukemia, 
MF refractory to JAK-inhibitory therapy and BPDCN. 
2. To determine the safety of IMGN901 in CD56 expressing hematological 
malignancies including but not limited to relapsed/refractory acute leukemia, 
MF refractory to JAK-inhibitor therapy and BPDCN. 
 
1.3 Exploratory Objective 
 
1.   To assess the response rate relative to the quantitative degree of CD56  
expression as assessed by flow cytometry. 
 
 
2.0 
BACKGROUND 
 
2.1  Acute Myeloid Leukemia (AML) 
 
2.1.1 Background  
AML is a malignancy of immature granulocytes or monocytes. The malignancy 
is characterized by accumulation of leukemic blastocytes and blockade of normal 
bone marrow production resulting in thrombocytopenia, anemia, and 
neutropenia. There are approximately 13,000 new cases of AML per year in the 
United States, with an estimated 10,000 deaths occurring in the same time 
period1. Almost all newly diagnosed cases, as well as deaths, will be in adults2. 
Standard treatment for AML includes systemic combination chemotherapy to 
control bone marrow and systemic disease. Treatment is generally divided into 
an induction phase, to attain remission, and a maintenance phase2. 
Approximately 60% to 70% of adults with AML can be expected to attain 
complete remission status following appropriate induction therapy. Remission 
rates in adult AML are inversely related to age, with an expected remission rate 
of >65% for those younger than 60 years. Increased morbidity and mortality 
during induction appear to be directly related to age3-5. 
 
2.1.2 Relapsed/ Refractory AML 


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Approximately, 30-40% of adults with AML fail to achieve CR with 1 or 2 
cycles of induction chemotherapy, and are deemed primary refractory. The 
outcome of patients with AML who are refractory to induction therapy are 
dismal, with low response rates to salvage chemotherapy and poor long-term 
survival 6-8. We have previously reported a dismal median OS of 3.8 months for 
patients with AML who are refractory to high dose cytarabine (HiDAC)-
containing induction therapy (defined as ≥ 1gm/m2 cytarabine per dose)7. 
Salvage therapy in such patient populations yielded a response rate of 18% and 
median response duration of 9 months.  
 
These results emphasize the need to explore alternate salvage regimens for 
patients with relapsed/refractory AML. The development of novel and effective 
anti-AML agents and/or combinations is crucial to improving the outcome of 
AML.  
 
2.1.3 CD56 expression in AML and high-risk myelodysplastic syndrome 
(MDS) 
Studies at MDACC by Seymour et al and Mann K et al showed CD56 in 22% 
and 20% of AML/ high-grade MDS and blast-phase CML, respectively9, 10. 
Other groups have noted CD56 expression in 20-24% of AML patients11-14. 
CD56 expression seems to be more frequent in t(8:21) AML: 54% in the series 
by Seymour et al, 55% in the series by Baer et al, and 68% in the series by Yang 
et al9, 15, 16. In t(8:21) the presence of CD56 expression did not impact the 
response rate but significantly shortened the CR duration and overall survival. 
CD56 expression is noted in 10-15% of acute promyelocytic leukemia (APL) 
and is strongly associated with inferior outcomes16, 17. APL patients with CD56 
have similar response rates but significantly shortened OS and DFS. CD56 
expression has also been associated with extramedullary disease and P-
glycoprotein mediated drug resistance12, 18. Patients expressing both CD56 and P-
glycoprotein seem to do exceptionally poorly. 
  
2.1.4 Impact of CD56 expression on outcome 
In non-8:21 and non-APL AML the impact of CD56 on outcome remains poorly 
defined. Raspaderi et al and Chang et al noted inferior OS in AML patients with 
CD56 expression12, 18. Conversely, Bona et al, Legrand et al, and Junca, et al 
noted no correlation with response and OS11, 13, 14. 
 
Patients with relapsed/refractory AML or high-risk MDS who express CD56 
may be suitable candidates for IMGN901.  
 
2.2 MF  
 
 2.2.1 Background 
MF has an estimated annual incidence of two to three cases per 100,000 persons 
in the USA19. Patients diagnosed with low-risk MF may survive for 15 years or 
longer, whereas the median life expectancy for intermediate-2 and high-risk 


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4
patients is only 3 years and <2 years, respectively20. Previous studies estimated 
the prevalence of MPNs at 75,000+ in the US21. Ruxolitinib is the only therapy 
that is currently approved for the treatment of patients with intermediate and 
high-risk MF. Two MD Anderson Cancer Center led phase III studies 
(COMFORT-I, COMFORT-II)22, 23 showed improvements in spleen size, 
symptom control and quality of life, resulting in the FDA-approval of ruxolitinib 
for patients with intermediate or high-risk myelofibrosis. However, the response 
rate to ruxolitinib single-agent is 42-45%. There is no standard of care post 
ruxolitinib or JAK inhibitor failure in MF.  
 
2.2.2 CD56 expression in MF 
CD56 is expressed on 17-34% of myelocytes and 39-69% of monocytes in MF. 
In controls, CD 56 was expressed on 0/20 control samples suggesting 
significantly increased expression in MF24. 
 
Patients with MF post JAK 2 inhibitors failure who express CD56 may be 
suitable candidates for IMGN901 
 
2.3 BPDCN 
 
2.3.1 Background  
Recently classified among “acute myeloid leukemia (AML) and related 
precursor neoplasms” in the 2008 World Health Organization (WHO) 
classification, BPDCN is a rare subtype of acute leukemia characterized by the 
clonal proliferation of precursors of plasmacytoid dendritic cells. The precise 
incidence of BPDCN is difficult to estimate due to constantly changing 
nomenclature and lack of precise defining criteria prior to the 2008 WHO 
classification system. BPDCN likely represent 0.7 percent of primary cutaneous 
skin lymphomas. However, cutaneous lymphoma registries likely underestimate 
the true incidence of BPDCN because a small but significant proportion of 
patients present without skin lesions. Tissue biopsies of involved sites reveal 
uniformly distributed, medium-sized blast cells that co-express CD4 and CD56, 
dendritic cell-associated markers like CD123, CD45RA, and TCL-1, but lack 
other lineage-specific markers25. Given its recent recognition as a distinct 
clinico-pathological entity, no standardized therapeutic approach has been 
established for BPDCN and the optimal therapy remains to be defined. A number 
of treatment modalities include ALL-like regimens (R-CHOP, HCVAD), AML-
like regimens (3+7), hematopoetic stem cell transplant have been studied. The 
overall survival rate is a dismal 12-14 months26.  
 
CD56 expression in BPDCN 
The high frequency of CD56 (>80%) expression and need for novel therapies in 
this disease makes it an ideal target for CD56 antibody therapy. 
 
 
2.4 IMGN901  


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2.4.1 Introduction 
Lorvotuzumab mertansine (IMGN901) is a humanized immunoglobulin (IgG1) 
kappamonoclonal antibody, conjugated through a disulfide linker, to the 
cytotoxic maytansinoid, DM1, with an average of 3.5 molecules DM1 per 
antibody. The monoclonal antibody is the humanized version of the murine N901 
monoclonal antibody engineered to bind specifically with the CD56 antigen, a 
member of the family of neural cell adhesion molecules (NCAMs). The target 
CD56 antigen is expressed on the surface of tumor cells of neuroendocrine 
origin, including small cell lung cancer (SCLC), carcinoid tumors and 
neuroblastomas, and on neuroectodermal tumors, such as astrocytomas, as well 
as many multiple myelomas (MM) and ovarian cancers. Additionally, CD56 is 
expressed on a number of hematological malignancies including acute leukemia, 
MF, BPDCN, NK-cell leukemia and others. 
 
IMGN901 acts by binding to the target antigen, CD56 on tumor cells and once 
bound, the conjugate is internalized and DM1 released. Within the cell, DM1 
disrupts microtubule assembly, leading to G2/metaphase arrest and ultimately 
cell death. 
 
2.4.2 Nonclinical Pharmacology, pharmacokinetics and toxicology 
 
2.4.2.1 Pharmacology 
Nonclinical pharmacology studies have demonstrated that the cytotoxicity 
of IMGN901 is restricted to CD56-positive tumor cell lines and it is active 
against SCLC, MM, and ovarian cancer as a single agent or in combination 
with standard-of-care anticancer agents. 
 
2.4.2.2. Pharmacokinetics (PK) 
Absorption, distribution, metabolism and excretion (ADME) studies 
demonstrate IMGN901is stable in circulation with an elimination phase 
half-life of one to two days. 
 
2.4.2.3. Nonclinical Toxicology 
Nonclinical safety evaluation of IMGN901 has focused on studies in 
cynomolgus monkey due to the lack of cross-reactivity to the antigen in 
non-primate species. The principal target organ for this species is the 
peripheral and central nervous system (spinal cord). In a single dose study, 
single bolus IV infusion of IMGN901 (152 and 456 mg/m2) was associated 
with dose-dependent minimal to mild findings of axonal degeneration of 
peripheral nerves and spinal cord. Repeat dosing was investigated on a 
weekly schedule (24 to 228 mg/m2 for six weeks) and daily schedule (2.4 to 
114 mg/m2 for five days). At the lowest weekly dose tested (24 mg/m2) 
minimal lesions in the spinal cord only were noted. Higher dose levels (> 24 
mg/m2 weekly or daily) were associated with lesions of the peripheral 
(sciatic and peroneal) and central (cervical, thoracic, and lumbar spinal) 


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nerves. 
 
The skin was also a target organ, with clinical changes relating to 
hyperkeratosis (peeling, flaking, cracking, etc.) after a single dose of 456 
mg/m2 or at repeated doses of 114 mg/m2 weekly or higher. Skin darkening 
correlated with increased amounts of melanin pigment and prominent 
melanocytes in the skin were observed following repeat doses of ≥ 24 
mg/m2 daily or ≥ 114 mg/m2 weekly. 
 
Changes in markers of hepatic function were limited to rises in 
transaminases and serum alkaline phosphatase (ALK) in the highest single 
dose tested (456 mg/m2) and transient rises in serum ALK activity with 
repeat daily doses of 114 mg/m2. There were no changes in markers of renal 
function. 
 
Treatment-related bone marrow suppression, leading to pancytopenia, and 
effects on the gastrointestinal (GI) system including enteropathy, affecting 
the small and large intestines, characterized by loss, dilatation and epithelial 
regeneration of intestinal crypts were seen in animals receiving the highest 
repeat daily dose of (114 mg/m2). 
 
2.4.3 Clinical pharmacokinetics and clinical study summaries 
 
2.4.3.1 Clinical pharmacokinetics 
Preliminary data from patients show that IMGN901 has a rapid clearance, 
with a half-life of 6 – 14 hours at doses ≤10 mg/m2. Clearance decreases 
with higher doses (≥ 40 mg/m2), with a half-life (t1/2) approaching 1 day. 
 
2.4.3.2 Clinical study summaries 
Because of the cytotoxic nature of DM1, studies with IMGN901in healthy 
volunteers were neither planned nor conducted. 
 
A total of 369 patients with cancer have been treated with at least one dose 
of IMGN901 in the clinical development program. Of the 369 patients 
treated, 198 received IMGN901 as a single agent, and 171 received 
IMGN901 in combination with other chemotherapeutic agents (either 
lenalidomide and dexamethasone [n=44] or carboplatin and etoposide 
[n=127]). The latter study includes a control arm comprised of 47 patients 
treated with carboplatin and etoposide alone. 
 
2.4.3.2.1. Single agent IMGN901 
IMGN901 has been investigated as a single agent in patients with SCLC 
(Study 001), CD56-positive solid tumors (Study 002) and MM (Study 003); 
all three of these studies are complete27, 28. A summary of available clinical 
data obtained in approximately 198 patients receiving single-agent 
IMGN901 (Studies 001, 002, 003) as of 31 March 2014, demonstrate the 


IMGN901 in hematological malignancies 
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7
following: 
  Most treatment
-related treatment-emergent adverse events 
(TEAEs) experienced with single-agent IMGN901 were low grade 
(Grade 1 or 2) and reversible. Treatment-related TEAEs occurring in 
≥ 20% of patients, in descending order of frequency, included 
neuropathy peripheral (31%), headache (30%), fatigue (29%), and 
nausea (27%). 
  As noted above, treatment
-related headache was commonly 
reported (30%), but most events were mild to moderate. Early in the 
clinical development program, severe, meningitis-like symptoms 
associated with headaches were reported; however, similar events 
have not been observed since implementation of a slowed infusion 
rate and routine steroid prophylaxis. 
  While the overall incidence of peripheral neuropathy and 
paraesthesia, irrespective of relationship to study treatment, was 33% 
and 9%, respectively, the Grade 3 incidence was low (3% and < 1% 
respectively), and there were no Grade 4 reports. 
 
The majority of changes in hematologic laboratory values observed with 
single-agent IMGN901 were mild to moderate. Across the three single-agent 
Phase 1 studies, at least one Grade 3 or Grade 4 hematologic abnormality 
was reported for 35% and 1% of patients, respectively. The most common 
Grade 3 abnormality was a decrease in lymphocyte count (29%). Most of 
the changes in chemistry laboratory values observed with single-agent 
IMGN901 were Grade 1 or 2 in intensity. At least one Grade 3 or Grade 4 
abnormality was reported in 46% and 8% of patients, respectively. The most 
common Grade 3 and/or 4 abnormalities were hyperglycemia (18%, all 
Grade 3) and gamma-glutamyl transferase (GGT) increased (12%, 10% 
Grade 3 and 2% Grade 4). 
  Skin changes noted in preclinical models have not been observed 
in the clinic. 
 
2.4.3.2.2 IMGN901 in combination regimens 
Additionally, IMGN901 has been investigated as part of a combination 
regimen in patients with MM in combination with lenalidomide and 
dexamethasone (Study 0005, closed to accrual) and in patients with SCLC 
in combination with carboplatin and etoposide (Study 0007, closed to 
accrual)29.  
 
A. IMGN901 in Combination with Lenalidomide and Dexamethasone 
(Study 0005) 
 


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been treated with lenalidomide (25 mg)/dexamethasone (40 mg) plus 
IMGN901 at doses of 75 mg/m2 (n=34), 90 mg/m2 (n=4), or 112 
mg/m2 (n=6). All patients (n=44) experienced at least one TEAE, with 
all also having at least one TEAE that was considered by the 
Investigator to be treatment-related. Overall, 91%, 21%, and 5% of 
patients have experienced at least one Grade 3, Grade 4, or Grade 5 
event, respectively. 
  Overall, the most common ty
pes of TEAEs were in the SOC of 
nervous system disorders (91%), with neuropathy peripheral being the 
most common AE (68%) and the most common treatment-related AE 
(66%). Other common TEAEs included fatigue (50%), diarrhea (43%), 
nausea (36%), pyrexia (34%), and cough (32%). 
  Not unexpectedly in this population of patients with a hematologic 
malignancy, all patients (n=44) experienced at least one hematologic 
laboratory abnormality. The most common Grade 3 or 4 hematologic 
abnormality was decreased hemoglobin, which was reported in all 
patients. The incidence of Grade 3 and 4 decreased hemoglobin was 
25% and 2%, respectively. Decreased lymphocyte count was reported 
in 77% of patients, with Grade 3 and Grade 4 incidences of 32% and 
14%, respectively. Fifty-seven percent and 46% of patients experienced 
decreased platelet count and neutrophil count, respectively, which may 
reflect effects of lenalidomide and dexamethasone. 
  Dose
-limiting toxicities (DLTs) were reported for six patients (18%) 
at the 75 mg/m2 dose level, and included Grade 2 peripheral 
neuropathy (three patients), Grade 2 tremor (one patient), and the 
following Grade 3 AEs in one patient each: tumor lysis syndrome and 
alanine aminotransferase (ALT) elevation. 
 
 
B. IMGN901 in Combination with Carboplatin and Etoposide (Study 
0007) 
 
Phase 1 
In Phase 1 of Study 0007, a total of 33 patients with advanced solid tumors, 
including SCLC, have been enrolled and treated with IMGN901, including 
six patients treated with IMGN901 60 mg/m2, carboplatin (AUC6) and 
etoposide; six patients treated with IMGN901 75 mg/m2, carboplatin 
(AUC6) and etoposide; three patients treated with IMGN901 75 mg/m2, 
carboplatin (AUC5) and etoposide; six patients treated with IMGN901 90 
mg/m2, carboplatin (AUC5) and etoposide; and twelve patients treated with 
IMGN901 112 mg/m2, carboplatin (AUC5) and etoposide. 
 


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being mild or moderate (Grade 1 or 2) in intensity and reversible. For 
most patients (97%), at least one TEAE was considered by the 
Investigator to be study treatment related. Treatment-related TEAEs 
occurring in > 10% of patients included anemia (55%), neuropathy 
peripheral (52%), thrombocytopenia (49%), fatigue (46%), nausea 
(33%), alopecia and neutropenia (each 27%), leukopenia (24%), 
lymphocyte count decreased and white blood cell count decreased (each 
21%), vomiting (18%), decreased appetite, febrile neutropenia, and 
neutrophil count decreased (each 15%), and diarrhea and lymphopenia 
(12% each). 
  All three patients treated with IMGN901 at a dose of 75 mg/m2, with 
carboplatin at an AUC 6 reported DLTs related to myelosuppression, 
including Grade 3 or 4 febrile neutropenia (two patients), Grade 4 
thrombocytopenia (two patients), and Grade 4 granulocytopenia (one 
patient). Therefore, the sponsor and investigators agreed to explore 
escalating doses of IMGN901 in combination with a reduced dose of 
carboplatin dose (AUC5). Escalation with IMGN901 continued to the 
maximum planned dose of (112 mg/m2). As only two of 12 patients 
reported a DLT at the 112 mg/m2 dose level, including Grade 3 lobar 
pneumonia and Grade 4 thrombocytopenia in one patient each, this 
dose was declared the recommended Phase 2 dose (RP2D), and this 
dose level was initially employed in the Phase 2 portion of Study 0007. 
The IMGN901 dose subsequently has been reduced to 90 mg/m2 due to 
an increased frequency of peripheral neuropathy among patients 
receiving IMGN901 at 112 mg/m2. 
 
Phase 2 
In Phase 2 of Study 0007, 94 patients with SCLC extensive disease have 
received IMGN901 in combination with carboplatin and etoposide (Arm 1); 
of these 94 patients, 50 received IMGN901 at a dose of 112 mg/m2 and 44 
received IMGN901 at a dose of 90 mg/m2. Additionally, 47 patients have 
received carboplatin and etoposide alone (Arm 2). 
  In March 2013, an interim aggregate analysis of safety data from 
Study 0007 revealed an increased frequency of peripheral neuropathy 
when IMGN901 is administered in combination with carboplatin and 
etoposide. A Data Monitoring Committee (DMC) meeting was held to 
review available safety data and the sponsor’s revised dose 
modification guidelines for patients experiencing peripheral 
neuropathy. The DMC concurred with the sponsor’s revised dose 
modification guidelines and recommended to lower the IMGN901 dose 
from 112 mg/m2 to 90 mg/m2. This change was implemented in April 
2013. As noted above, of the 94 patients treated in Arm 1, 50 received 
IMGN901 112 mg/m2 and 44 received IMGN901 90 mg/m2. 


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Based on data through 31 March 2014, the rate of peripheral 
neuropathy events was 79% in Arm 1 versus 13% in Arm 2. 
Comparison of the rate of peripheral neuropathy events by IMGN901 
dose in Arm 1 showed that lowering the dose of IMGN901 to 90 
mg/m2 and institution of management procedures for such events was 
associated with a lower incidence of peripheral neuropathy events of 
71% compared to 86% at the higher dose of 112 mg/m2. Furthermore, 
the Grade 3 incidence of peripheral neuropathy events was lower with 
IMGN901 90 mg/m2 than with 112 mg/m2 (11% versus 36%, 
respectively). No Grade 4 peripheral 
neuropathy events were reported. 
 
Review of TEAEs by study arm, regardless of IMGN901 dose, showed 
that TEAEs occurring at a ≥ 10% higher incidence in Arm 1 than in 
Arm 2 included neuropathy peripheral (61% versus 9%); fatigue (50% 
versus 30%); asthenia (32% versus 21%); constipation (32% versus 
19%); diarrhea (31% versus 17%); paraesthesia (22% versus 4%); 
insomnia (19% versus 9%); and dyspepsia (14% versus 0%). 
  Review of TEAEs by IMGN901 dose in Arm 1 showed that TEAEs 
occurring at a > 10% higher incidence with IMGN901 112 mg/m2 than 
with 90 mg/m2 included neutropenia (58% versus 46%); nausea (50% 
versus 36%); alopecia (38% versus 18%); paraesthesia (30% versus 
14%); arthralgia (24% versus 11%); white blood count decreased (14% 
versus 2%); and mucosal inflammation (20% versus 7%). 
  Most patients (95%) in the IMGN901 arm experienced at least one 
study treatment-related TEAE (for all grades). Study treatment-related 
TEAEs occurring in > 10% of IMGN901-treated patients included 
neuropathy peripheral (61%); neutropenia (46%); fatigue (43%); 
anemia (40%); nausea (35%); thrombocytopenia (28%); decreased 
appetite (26%); asthenia and diarrhea (each 25%); paraesthesia (22%); 
alopecia (16%); neutrophil count decreased and platelet count 
decreased (each 14%); hypomagnesemia (13%); and arthralgia, 
constipation, and vomiting (each 12%). 
 
Thirty-one (33%) IMGN901-treated patients experienced a total of 52 
SAEs that were considered by the Investigator to be at least possibly 
related to study drug, most commonly including febrile neutropenia 
(7%); neutropenia, neuropathy peripheral; pneumonia, and septic shock 
(each 4%); and neutropenic sepsis and sepsis (each 3%). 
 
The incidence of infectious serious adverse events including fatal 
outcome was higher in Arm 1 (16%) compared to Arm 2 (11%). A 
majority of these events occurred within the first 2 cycles (42 days) of 


IMGN901 in hematological malignancies 
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study treatment. The most common infectious events in Arm 1 were 
pneumonia (6%) and septic shock (5%). The overall rate of death from 
a serious infectious event was 11% for Arm 1 compared to 4% for Arm 
2. 
 
Sixteen (17%) patients in Arm 1 of Study 0007, Phase 2, died on-study 
(within 28 days of last study treatment). The causes of death among 
these 16 patients were pneumonia (four patients); sepsis (three 
patients); and acute severe respiratory failure, cardiac arrest, disease 
progression, gastrointestinal bleeding, hypotension, pleural effusion, 
pyrexia, septic shock and suicide (one patient each). The cause of death 
was considered to be study treatment-related for eight (9%) patients, 
including sepsis (three patients); pneumonia (two patients), and 
hypotension, pyrexia and septic shock (one patient each). 
 
Further details can be found in the IMGN901 investigator brochure 
(Appendix C), which contains comprehensive pharmacology, toxicology, 
pharmacokinetics, pharmacodynamics, metabolism, preclinical, and clinical 
efficacy and safety data information 
 
 
3.0  STUDY DESIGN: 
 
3.1 The study will be a phase II, single-institution, open-label, non-randomized, 
parallel group clinical trial. The study will include three separate cohorts to be 
enrolled simultaneously. A response and toxicity summary for each treatment 
cohort (1, 2 and 3) will be submitted to the IND Medical Monitor per the 
guidelines found in the statistical section 12.0. 
 
1. CD56 expressing hematological malignancies (Cohort 1): Patients with 
confirmed CD56 expressing hematological malignancies including but not limited 
to AML, high-risk MDS, natural-killer leukemia, acute lymphoblastic leukemia, 
accelerated and blast-phase CML who have failed prior therapy or for which no 
standard therapy exists. Relapsed/ refractory status defined by the failure of at 
least one prior cycle of chemotherapy (including but not limited to cytotoxic 
chemotherapy, hypomethylator therapy, FLT3-inhibitor therapy, stem cell 
transplant or stem cell therapy investigational therapy, targeted therapy, immune-
based therapy, and others). 
 
2. MF (Cohort 2): To be eligible for this cohort patients must have intermediate or 
high-risk MF (either primary MF, post-polycythemia MF, or post-essential 
thrombocythemia MF), have confirmed CD56 expression and have been on 
ruxolitinib or JAK-inhibitor therapy for at least 12 weeks and deemed refractory 
or sub-optimal responders in the opinion of the treating physician. 
 
3. BPDCN (cohort 3): Patients with a pathological diagnosis of BPDCN and 


IMGN901 in hematological malignancies 
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12
confirmed CD56 expression.  
 
 
4.0 PATIENT SELECTION 
 
Patients must have baseline evaluations performed prior to the first dose of study 
drug and must meet all inclusion and exclusion criteria. Results of all baseline 
evaluations, which assure that all inclusion and exclusion criteria have been 
satisfied, must be reviewed by the Principal Investigator or his/her designee prior 
to enrollment of that patient. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient prior to initiating treatment or 
any study-specific procedures. The following criteria apply to all patients enrolled 
onto the study unless otherwise specified. 
 
4.1 
Inclusion Criteria 
 
1. Patients with CD56 expressing hematological malignancy, as follows: 
 
A. Cohort 1: CD56 expressing hematological malignancies including but not 
limited to AML, high-risk MDS, natural-killer leukemia, acute lymphoblastic 
leukemia, accelerated and blast-phase CML who have failed prior therapy or 
for which no standard therapy exists 
B. Cohort 2: Patients with MF (either primary MF, post-polycythemia MF, or 
post-essential thrombocythemia MF) and CD56 expression who have been on 
ruxolitinib or JAK-inhibitor therapy for at least 12 weeks and deemed 
refractory or sub-optimal responders in the opinion of the treating physician 
C. Cohort 3: Patients with pathological diagnosis of BPDCN with CD56 
expression (frontline and relapsed/refractory). 
 
2. Any level of CD56 expression will be considered sufficient for enrollment on this 
study.  
 
3. Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy 
(e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is 
allowed.  
 
4. Age >/=18 years 
 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status  </= 2 
 
6. Adequate organ function: total bilirubin ≤ 2 times upper limit of normal (x ULN) 
(≤ 3 x ULN if considered to be due to leukemic involvement or Gilbert’s 
syndrome); aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
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13
≤ 2.5 x ULN (≤ 5.0 x ULN if considered to be due to leukemic involvement); 
serum creatinine ≤ 2 x ULN, amylase and lipase ≤ 2 x ULN .  
 
7. In the absence of rapidly progressing disease and after discussion with the PI, the 
interval from prior treatment to time of IMGN901 administration will be at least 2 
weeks or at least 5 half-lives for cytotoxic/noncytotoxic agents. The half-life be 
based on published pharmacokinetic literature (abstracts, manuscripts, 
investigator brochure’s, or drug-administration manuals) and will be documented 
in the protocol eligibility document. For prior monoclonal antibody therapy the 
interval from prior monoclonal antibody treatment to time of IMGN901 
administration will be at least 2 weeks. The use of chemotherapeutic or anti-
leukemic agents other than hydroxyurea (as defined in the protocol) is not 
permitted during the study with the exception of intrathecal (IT) therapy for 
patients with controlled CNS leukemia at the discretion of the PI. Hydroxyurea is 
allowed prior to the initiation of IMGN901 and during the first 3 cycles, either 
prior to or concomitantly with IMGN901 administration to control leukocytosis.  
 
8. Women of childbearing potential must practice contraception. Females of 
childbearing potential: Recommendation is for 2 effective contraceptive methods 
during the study. Adequate forms of contraception are double barrier methods 
(condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or 
foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and 
tubal ligation. Male patients with female partners who are of childbearing 
potential: Recommendation is for male and partner to use at least 2 effective 
contraceptive methods, as described above, during the study. 
 
9. Females must be surgically or biologically sterile or postmenopausal 
(amenorrheic for at least 12 months) or if of childbearing potential, must have a 
negative serum or urine pregnancy test within 72 hours before the start of the 
treatment  
 
10.  Patients must provide written informed consent.  
 
11. Women of childbearing potential must agree to use an adequate method of 
contraception during the study and until 3 months after the last treatment. Males 
must be surgically or biologically sterile or agree to use an adequate method of 
contraception during the study until 3 months after the last treatment. 
 
Adequate methods of contraception include: 
 Total abstinence when this is in line with the preferred and usual lifestyle of 
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study 


IMGN901 in hematological malignancies 
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14
treatment. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female patients on 
the study, the vasectomized male partner should be the sole partner for that 
patient 
 Combination of any of the two following (a+b or a+c or b+c) 
a) Use of oral, injected or implanted hormonal methods of contraception or 
other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal 
hormone contraception 
b) Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c) Barrier methods of contraception: Condom or Occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal 
suppository 
 
       In case of use of oral contraception, women should have been stable on the 
same pill before taking study treatment. 
 
Note: Oral contraceptives are allowed but should be used in conjunction with a 
barrier method of contraception due to unknown effect of drug-drug interaction. 
 
        Women are considered post-menopausal and not of child bearing potential if 
they have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation 
at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential. 
 
4.2 
Exclusion Criteria 
 
1.   Patients with known allergy or hypersensitivity to IMGN901. 
 
2.   Patients who have previously been treated with IMGN901. 
 
3.    Patients with symptomatic CNS leukemia or patients with poorly controlled CNS 
leukemia.  
 
4.    Peripheral neuropathy >grade 2.  
 
5.    Active or clinically symptomatic chronic pancreatitis or disease affecting 
pancreas.  
 
6.    Neurologic disease including multiple sclerosis, Eaton-Lambert syndrome, 
demyelination.  
 


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15
7.    Significant cardiac disease including myocardial infarction or unstable angina 
within 6 months, uncontrolled hypertension despite medical therapy (defined as 
blood pressure >160/110 in spite of adequate medical therapy), active and 
uncontrolled congestive heart failure NYHA class III/IV, stroke within preceding 
6 months. 
 
8.    Patients with known Human Immunodeficiency Virus seropositivity will be 
excluded.  
 
9.    Known to be positive for hepatitis B by surface antigen expression. Known to 
have active hepatitis C infection (positive by polymerase chain reaction or on 
antiviral therapy for hepatitis C within the last 6 months). Known to be active 
CMV infection or herpes zoster infection. 
 
10.  Pregnant or breast feeding (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation, confirmed 
by a positive β-HCG laboratory test.  
 
11.  Patients with any concurrent severe and/or uncontrolled medical condition or 
active uncontrolled systemic infection as determined by the investigator. 
 
12. Patients who have had any major surgical procedure within 14 days of Day 1. 
 
13.  Patients unwilling or unable to comply with the protocol. 
 
 
5.0 
TREATMENT PLAN: 
 
5.1 
Schedule 
 
All patients will be registered through CORe. 
 
IMGN901 will be administered intravenously at a dose of 100 mg/m2 on 
day 1 and 8 of a 21-day cycle. All doses may be +/- 2 days. This dose and 
schedule is below the established MTD of single agent IMGN901 in 
multiple myeloma studies. In the myeloma studies by Chanan-Khan et al. 
the MTD of single-agent IMGN901 was established to be 112mg/m2 
administered via intravenous (IV) infusion once weekly for two weeks 
every three weeks28.  
 
            For further details regarding dose-calculation of IMGN901, 
preparation and dispensing of IMGN901, administration of IMGN901, 
patient monitoring during infusion and treatment of IMGN901 related 
infusion reactions please see the dosing procedure manual (Appendix D). 
 


IMGN901 in hematological malignancies 
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16
5.1.1.1 Cycles may be started early (but not earlier than day 19) for 
patients with active  leukemia (i.e. bone marrow blasts > 5% 
or peripheral or peripheral blood blast >5%) if judged in the 
best interest of the patient.  
 
5.1.1.2 Subsequent cycles may be delayed at the discretion of the 
investigator for recovery of drug-related toxicity or other 
medical conditions (e.g. infections). Delays in start of 
subsequent cycles greater than 56 days will be acceptable 
only for patients who are deriving clinical benefit and after 
discussion with the principal investigator of potential 
risk/benefit ratio.   
 
5.1.1.3 Subsequent courses may be administered regardless of 
peripheral blood counts during the first 4 cycles and/or if 
bone marrow blasts >5% or peripheral blood blast >5%). If 
the peripheral counts do not recover but there is evidence of 
active leukemia (i.e. bone marrow blasts >5% or peripheral 
blood blast >5%), subsequent cycles can be administered at 
the discretion of the treating physician not earlier than 19 
days after the prior cycle..  
 
5.1.1.4 If prolonged myelosuppression (more than 56 days) with 
evidence of a hypocellular marrow (marrow cellularity less 
than 5% without evidence of leukemia) is observed, 
IMGN901 will be discontinued. If the peripheral counts do 
not recover but there is evidence of residual leukemia in the 
bone marrow, subsequent cycles can be administered at the 
discretion of the treating physician not earlier than 19 days 
after the prior cycle. This will apply both after 4 cycles and 
after remission is achieved. Delays in start of subsequent 
cycles greater than 56 days will be acceptable only for 
patients who are deriving clinical benefit and after 
discussion with the principal investigator of potential 
risk/benefit ratio.   
 
5.1.1.4 For patients who discontinue therapy, the reason for 
treatment discontinuation will be captured.   
 
5.2 
IMGN901 administration 
For use in clinical trials, IMGN901 is supplied by Immunogen, Inc. 
as single-use vials in strengths of 100 mg and is formulated for 
intravenous (IV) administration. IMGN901 drug product is a clear, 
colorless liquid formulation that contains the bulk active drug 
substance (huN901 antibody conjugated to DM1) and other inactive 
ingredients (excipients). The drug product formulation is 5.0 mg/mL 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
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17
IMGN901, 10 mM succinate, 250 mM glycine, 0.5% (w/v) sucrose, 
0.01% (w/v) Polysorbate 20, pH 5.5. The final product vial is stored 
at 2 to 8°C (36 to 46°F). Details of IMGN901 administration are 
provided in the IMGN901 Pharmacy Manual (Appendix D). 
Variations in infusion times of IMGN901 due to minor differences in 
IV bag overfill/underfill and institutional procedure on flushing 
chemotherapy lines will not result in protocol deviation. All infusion 
times are considered approximate. 
 
Unused or expired IMGN901 will be safely disposed according to 
MD Anderson pharmacy standard guidelines. 
 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment 
may continue until one of the following criteria applies: 
 
1. 
Clinically significant progressive disease 
 
2. 
Intercurrent illness that prevents further administration   of 
treatment, 
 
3. 
Patient request 
 
4. 
General or specific changes in the patient's condition render 
the patient unacceptable for further treatment in the 
judgment of the investigator. 
 
5. 
Unacceptable toxicity that in the opinion of the investigator 
makes it unsafe to continue therapy. 
 
5.3.1 It is planned that up to a total of 12 cycles of therapy will be 
administered for patients deriving benefit from this regimen. 
Continuation of therapy for patients completing 12 cycles of therapy 
may be considered on a case-by-case basis after discussion with the 
principal investigator.  
 
5.3.2 
A minimum of 1 full course [defined as the administration of at 
least 2 doses of IMGN901 on days 1 (+/-2 days) and 8 (+/-2 days) of 
the 21 day cycle] will be required for a patient to be considered as 
having received an adequate trial to evaluate efficacy. All patients 
who receive two doses of IMGN901 during the first cycle will be 
evaluable. All patients receiving at least one dose of any of 
IMGN901 will be considered evaluable for toxicity.   
 
5.4 Supportive care 


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18
Supportive care measures including blood products, infection 
prophylaxis and growth factors will be administered according to 
institutional and Leukemia Department guidelines. 
 
5.5   Concomitant medications 
If considered necessary for the subject’s wellbeing, drugs for 
concomitant medical conditions or for symptom management may be 
given at the discretion of the investigator. The investigator’s decision to 
authorize the use of any drug other than study drug should take into 
account subject safety, the medical need, the potential for drug 
interactions, the possibility for masking symptoms of a more significant 
underlying event, and whether use of the drug will compromise the 
outcome or integrity of the study.  
 
Recommendations with regard to specific types of concomitant 
therapies, supportive care, diet and other interventions are as follows:  
 
Concomitant medications are recommended as prophylaxis for nausea, 
vomiting, and infections, and are allowed for managing 
myelosuppression as shown in Table 1. Myelosuppression is expected 
in patients with AML due to underlying disease, as well as due to the 
therapy (IMGN901), or both. Most patients have neutropenia, 
thrombocytopenia, or both at study entry. Significant or life-threatening 
myelosuppression may be managed with growth factor support 
including G-CSF, GM-CSF and platelet growth factors and 
erythropoeitn/darbopoetin/blood transfusion according to institutional 
standard of care, American Society of Clinical Oncology (ASCO) 
Practice Guidelines, and/or NCCN Practice Guidelines.  
 
Infections secondary to myelosuppression are common in patients with 
AML, and may be related to underlying disease, chemotherapy, or both. 
Therefore, the use of prophylactic antibiotics, antifungal agents, and 
antiviral agents is recommended according to institutional standards.  
 
Since the effect of IMGN901 may be delayed, patients with high WBC 
counts may receive hydroxyurea prior to study entry. Hydroxyurea is 
allowed before the start of study therapy and during the first 3 cycles to 
control leukocytosis. Hydroxyurea use would be recorded in the CRF. 
Concurrent therapy for CNS prophylaxis or continuation of therapy for 
controlled CNS disease is permitted. With the exception of these 
agents, concomitant systemic chemotherapy or radiation therapy is not 
permitted. Subjects are not allowed to participate concurrently in any 
other therapeutic clinical study to treat the primary disease process. 
Supportive care and laboratory protocol participation is allowed. 
 
 


IMGN901 in hematological malignancies 
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19
Subjects may be receiving systemic corticosteroids (daily doses ≤10 mg 
of prednisone or equivalent if indicated for adrenal replacement or 
antiemetic therapy), topical, or inhaled corticosteroids at study 
enrollment. They may receive systemic, topical, inhaled, or enteric 
corticosteroids while on study without limitation if they develop 
conditions that require corticosteroid therapy; such subjects are not 
required to discontinue study participation. 
 
All ongoing medications and therapies (including herbal products, 
nutritional supplements, and nontraditional medications) at screening 
will be considered prior medications. Concomitant medication data will 
not be collected or entered into the case report form other than 
hydroxyurea and cytarabine; however, the subject’s medication record 
will contain a list of concomitant medications. If a prohibited 
medication is inadvertently administered/ taken by the patient, the 
patient may remain on study as long as the prohibited medication is 
discontinued as soon as feasible. If a prohibited medication is 
considered essential for the patient well being, continuation on study 
with concomitant administration of such medication(s) will need to be 
discussed with and approved by principal investigator.  
Table 1: Instructions for the use of concomitant medications and therapies 
Category of Use 
Medication 
Comment on Use 
Restriction on Use 
Recommended 
Prophylactic 
antibiotics, 
antifungal agents, 
and antiviral agents 
Strongly 
encouraged 
None 
 
Antiemetic agents 
According to 
standard of care at 
MDACC 
None 
Allowed 
Oral allopurinol or 
rasburicase 
At investigators 
discretion 
 
None 
 
Leukapheresis 
According to 
standard of care at 
MDACC 
 
Before induction 1 
day 1 only 
 
Red blood cell 
transfusion 
According to 
standard of care at 
MDACC  
 
None 
 
Platelet transfusion 
According to 
standard of care at 
MDACC  
 
None 
 
White blood cell 
transfusion 
At investigators 
discretion according 
None 


IMGN901 in hematological malignancies 
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20
to standard of care 
at MDACC 
 
 
Myeloid growth 
factors or platelet 
growth factor 
At investigators 
discretion according 
to standard of care 
at MDACC 
 
None 
 
Erythropoietin or 
darbepoetin 
 
At investigators 
discretion 
 
None 
 
Any other 
medication for 
supportive care 
At investigators 
discretion according 
to standard of care 
at MDACC  
None 
 
 
6.0 
DOSING DELAYS/DOSE MODIFICATIONS 
        
Table 2: Dosing schema 
Dose level 
IMGN901 
0 
100 mg/m2 day 1,8 
-1 
80 mg/m2 day 1,8 
-2 
60 mg/m2 day 1, 8 
-3 
40 mg/m2 day 1, 8 
 
6.1 
Toxicity Directly Attributable to Study Drug 
 
Patients experiencing unacceptable clinically significant toxicity directly 
attributable to the IMGN901 should temporarily stop treatment according 
to the guidelines in the dose adjustment schema. 
 
6.2 
Toxicity Grading 
 
Toxicity grading will be according to the NCI CTCAE, version 4.0 
(Appendix F). To prevent unnecessary morbidity, the following guidelines 
for dose adjustment for drug-related toxicities are recommended.  
 
6.3 
Dose Reductions 
 
Dose reductions for non-hematologic toxicity possibly related to study 
drugs should be performed according to table 3 below. 
 
Toxicity 
Grade 
Actions 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
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21
Table 3. Dose adjustments for non-hematologic drug-related AEs, 
clinically significant in the opinion of the investigator 
 
6.3.1 Peripheral neuropathy: For peripheral neuropathy hold therapy for 
grade 2 and then restart at lower dose once neuropathy subsides to 
grade 1. For grade 1 peripheral neuropathy do not hold dose but 
consider administering the subsequent dose at one dose level 
reduction. 
 
6.3.2 Hepatotoxicity: A reduction in the dose of IMGN901 is 
recommended in cases of drug-related hepatotoxicity, as follows: 
Patients with any instance of drug-related grade 4 hepatotoxicity 
will permanently discontinue therapy with IMGN901.  
 
Dose-modifications 
for 
drug-related 
increased 
serum 
transaminases (AST/ALT) 
Grade 2(>3.0 to ≤5 
x ULN) 
Grade 3(>5 to ≤20 x 
ULN) 
Grade 4 (>20 x ULN) 
Treat at same dose 
level 
Do not administer 
IMGN901 
until 
AST/ALT recovers 
to Grade ≤ 2, and 
then reduce one dose 
level.  
Permanently 
discontinue 
IMGN901. 
 
Non-hematological 
(excludes myalgia/ 
arthralgia responding to 
treatment, inadequately 
treated vomiting and 
diarrhea, or electrolyte 
abnormalities unless 
not responding to 
optimal 
supplementation) 
3 or 4 
Hold therapy until recovery to 
Grade 1, then re-start with a 
one dose level reduction. If 
toxicity recurs, hold therapy 
until recovery to grade 1, 
then re-start and reduce one 
additional dose level. Patients 
requiring dose reductions 
below dose level -3 will be 
taken off-protocol. 
Non-hematological 
(excludes myalgia/ 
arthralgia responding to 
treatment, inadequately 
treated vomiting and 
diarrhea, or electrolyte 
abnormalities unless 
not responding to 
optimal 
supplementation)  
Persistent 2 considered 
clinically significant or 
upon patient’s request  
Consider holding therapy until 
recovery to Grade 1, then re-
start and reduce one dose level. 
If toxicity recurs again, therapy 
may be held until recovery to 
grade 1, then re-start and 
reduce one additional dose 
level.  Patients requiring dose 
reductions below dose level -3 
will be taken off-protocol. 


IMGN901 in hematological malignancies 
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22
                                   Dose-modifications for drug-related hyperbilirubinemia 
Grade 2(>1.5 to ≤3 
x ULN) 
Grade 3(>3 to ≤10 x 
ULN) 
Grade 
4 
(>10 
x 
ULN) 
Do not administer 
IMGN901 until total 
bilirubin recovers to 
Grade ≤ 1, and then 
treat at same dose 
level. 
Do not administer 
IMGN901 until total 
bilirubin recovers to 
Grade ≤ 1, and then 
treat at same dose 
level. 
Permanently 
discontinue 
IMGN901. 
 
Permanently discontinue IMGN901 treatment in patients with 
drug-related serum transaminases > 3 × ULN and concomitant 
total bilirubin > 2 × ULN. 
Permanently discontinue IMGN901 in patients diagnosed with 
drug-related nodular regenerative hyperplasia (NRH) 
 
6.3.3 Patients in whom the toxicity occurs or persists beyond the planned 
completion of drug administration for the cycle will have the dose 
reductions implemented in subsequent cycles provided the toxicity 
has resolved as specified in the table above.  
 
6.3.4 If the criteria to resume treatment are met, the subject should 
restart treatment at the next scheduled time point per protocol. 
However, if the treatment is delayed past the next scheduled time 
point per protocol, the next scheduled time point will be delayed 
until dosing resumes.  
 
6.4 
Myelosuppression 
 
 Patients with acute leukemia’s usually present with abnormal 
peripheral blood counts at the time therapy is started and 
myelosuppression is an expected event during the course of 
therapy for acute leukemia’s. Thus, no dose adjustments or 
treatment interruptions for myelosuppression will be planned for 
the first 4 cycles and/or in the presence of any residual leukemia. 
After that, treatment interruptions and dose adjustments may be 
considered according to the following guidelines only when there 
is no evidence of active leukemia.  
 
 Patients with a complete response (e.g., only if <5% 
blasts in the bone marrow or cytopenias not considered 
to be related to leukemia) and pre-cycle counts of 
neutrophils >1x109/L and platelets >50 x109/L who 
have sustained low counts of neutrophils <0.5 x109/L or 
a platelet count <20 x 109/L for more than 2 
consecutive weeks in the current cycle, may have the 


IMGN901 in hematological malignancies 
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23
treatment with IMGN901 interrupted at the discretion 
of the treating physician after discussing with the PI 
until neutrophils recover to ≥0.5 x109/L and platelets to 
≥30 x109/L.  
 
 If there are persistent peripheral blood blasts, or the 
bone marrow shows >5% blasts or any evidence of 
leukemia, treatment may be continued regardless of 
neutrophil and platelet count with supportive care as 
needed. Dose-interruptions of IMGN901 in these 
patients should be considered on an individual case and 
discussed with the PI.  
 
 Patients with a response (no evidence of leukemia) and 
pre-cycle counts of neutrophils <1x109/L and platelets 
<50 x109/L may be continued regardless of neutrophil 
and platelet count with supportive care as needed. 
Dose-interruptions 
in 
these 
patients 
should 
be 
considered on an individual case and discussed with the 
PI. 
 
6.4 Modifications of dose schedules other than the above will be allowed 
within the following guidelines: 
 
6.4.1 Further dose reductions can be made to keep clinically significant 
IMGN901-related toxicity grade < 2. However, the lowest 
acceptable dose is 40 mg/m2 on days 1 and 8.  
 
6.4.2 Dose adjustments by more than 1 dose level at a time (e.g., from 
100 mg/m2 to 60 mg/m2 mg on days 1 and 8) can be considered 
when judged in the best interest of the patient (e.g., neutropenia 
with sepsis, bleeding requiring platelet transfusions) when toxicity 
has resolved. The reason for this reduction will be discussed with 
the PI or Co PI and documented in the medical record. 
 
6.4.3 A patient who has had a dose reduction because of any of the 
reasons mentioned above may have their dose escalated provided 
the toxicity requiring dose adjustments has resolved to ≤ grade 1. 
Escalation will be made by 1 dose-level increment only, and not 
more frequent than every 21 days.  
 
6.4.4 Treatment interruptions and dose modifications other than the ones 
mentioned above can be considered after discussion with the PI 
and proper documentation of the rationale. 
 
6.4.5 All dose adjustments will be made according to the protocol unless 


IMGN901 in hematological malignancies 
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24
otherwise specified. 
 
7.0      AGENT FORMULATION AND PROCUREMENT (Appendix D) 
 
7.1 Appearance: 5 mg/mL Formulation: Clear, colorless solution, essentially free 
from visible particulate matter 
 
7.2 Active Ingredient: huN901-DM1 
 
7.3 Purity: ≥ 95% as determined by size-exclusion High Performance Liquid 
Chromatography (HPLC)  
 
7.4 Molecular Weight: About 146,145 Da (deglycosylated mass of huN901 
antibody as 
determined by mass spectrometry) plus [737.5]n (mass of attached DM1 with 
linker, n = ~3.5 drug linked per antibody) 
 
7.5 Container/Closure: Single use 20 mL/20 mm Type I clear glass vials, with a 
20 mm coated stopper. 
 
7.6 Formulation and strength: IMGN901 is a solution for IV infusion supplied 
in single use vials at a protein concentration of 5.0 mg/mL in buffered solution 
(pH 5.5). The drug product formulation is 5.0 mg/mL IMGN901, 10 mM 
succinate, 250 mM glycine, 0.5% (w/v) sucrose, 0.01% (w/v) Polysorbate 20, pH 
5.5. The final product is presented in 20 mL clear glass, sterile vials, Type I. Each 
vial is sealed with a Flurotec®-coated stopper. 
Each vial contains 20 mL IMGN901 solution for infusion. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration, whenever solution and container permit. 
Only clear, colorless solutions should be administered. If the IMGN901 solution 
is not clear and colorless it should be returned to ImmunoGen. Patients should be 
observed for at least one hour after completion of each infusion or as instructed in 
the study specific protocol. 
 
7.7 Storage and handling: The product should not be shaken or frozen; it should 
be stored at 2 to 8°C (36 to 46°F) and allowed to equilibrate to ambient 
temperature for 15 minutes before use. The shelf-life at 2 to 8°C (36 to 46°F) is 
provided on the vial-label, or is provided on the Certificate of Analysis provided 
to the site with each shipment of IMGN901 vials. 
 
7.8 Preparation and premedications: IMGN901 will be administered per dose 
and schedule relevant to each investigational study. IMGN901 should be prepared 
by a pharmacist or other appropriately licensed and authorized personnel and 
administered as described in the study specific protocol or pharmacy manual.  
 


IMGN901 in hematological malignancies 
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25
The following steps should be carried out in a laminar flow hood, using aseptic 
technique throughout:  Take the required number of vials from cold storage 15 minutes before required 
to allow solution to reach ambient temperature (18 to 25°C).  Draw up the appropriate volume of IMGN901 solution into a suitably sized 
sterile syringe.  Transfer the require
d volume of IMGN901 to a sterile infusion bag or syringe. 
  Note: (5 mg/mL concentration) is diluted 1:1 in normal saline or 5% dextrose
 
prior to adding to the infusion bag.  Do not leave the prepared drug in direct sunlight.
 
 
Administer IMGN901 IV infusion within eight hours of preparation using a low 
protein binding 0.22-micron filter. 
 
In early studies of IMGN901, patients reported headache with aseptic meningitis-
like symptoms. Since the introduction in protocols of a corticosteroid-based 
premedication, there have been no further reports of these AEs in the later studies. 
Premedication with hydrocortisone 100 mg IV or equivalent corticosteroid-based 
agent should be implemented prior to every infusion of IMGN901. 
 
7.9 Drug Infusion: The drug will be administered via an intravenous tubing set 
with a 0.2 micron in-line filter. In the case that an in-line filter is unavailable, a 
0.2 micron filter unit may be attached to the administration set.  
 
The infusion tubing may be primed with 0.9% normal saline solution or may be 
primed with the drug making sure that no drug is wasted in doing so. Following 
the infusion, the IV line should be flushed with 0.9% normal saline solution) as 
required to ensure delivery of the full dose. 
 
Details of the dose level and the total dose to be administered will be documented 
in the source records.  For every infusion, the time started and stopped for each 
infusion rate, volume infused at each rate, total volume infused, the times of any 
interruptions/decreases, and the reason if an infusion is stopped prematurely 
should be documented on the Medical Administration Record. .  
 
For the initial infusion, IMGN901 is to be administered at a rate of 1 mg/min for 
the first 15 minutes. Provided the patient tolerates this rate of infusion, the rate 
can be increased to 3 mg/min. If patient tolerates the Cycle 1 Day 1 infusion, all 
subsequent infusions may be delivered at the 3 mg/min rate. Infusion time will 
vary depending on rate of infusion and may be several minutes to several hours. 
 
Management of Potential IMGN901 Infusion Reactions 
Some patients treated with IV infusions of monoclonal antibodies have 
experienced concurrent infusion-related reactions with signs or symptoms that can 
be classified as acute allergic/hypersensitivity reactions or cytokine release 


IMGN901 in hematological malignancies 
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syndrome (see NCI CTCAE, version 4.0).  The signs and symptoms include 
headache, fever, facial flushing, pruritus, myalgia, nausea, chest tightness, 
dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, shivers, 
hypertension, lightheadedness, hypotension, palpitations, and 
somnolence.  Anaphylaxis might occur at any time during an infusion.  In 
addition, the re-administration of some monoclonal antibodies has been associated 
with serum sickness-like reactions manifesting 1 to 14 days after drug 
administration. 
 
Before any infusion is started, appropriate medical personnel, medication (e.g. 
epinephrine, inhaled beta agonists, antihistamines, and corticosteroids) and other 
required resources to treat anaphylaxis must be readily available. Patients 
experiencing a reaction during the administration of study agent should be treated 
according to institutional guidelines.  
 
The infusion must be stopped immediately if ≥ Grade 2 allergic/hypersensitivity 
reactions (including drug fever) or ≥ Grade 3 cytokine release syndrome/acute 
infusion reaction occurs.  The Sponsor or designee must be notified within 24 
hours of any infusion reaction requiring interruption of study agent. 
For a mild or moderate infusion-related reaction, medication with antihistamine 
(e.g., with diphenhydramine, 25 to 50 mg orally or equivalent) and 
acetaminophen (650 mg orally or equivalent) may be considered and, if the signs 
and symptoms have resolved with the above medications, the infusion may be 
restarted. 
 
If the event is clearly anaphylaxis, then SQ epinephrine (1/1000, 0.3-0.5 mL or 
equivalent) should be considered.  In the case of bronchospasm, inhaled beta 
agonist also should be considered.  The infusion rate may also be lowered if 
clinically indicated.  Patients experiencing an infusion reaction should be 
observed in the clinic until resolution of the reaction, or until in the Investigator’s 
best judgment, it is considered safe to allow the patient to be discharged.  Patients 
administered antihistamine for the treatment or prevention of infusion reactions 
should be given appropriate warnings about drowsiness and impairment of driving 
ability prior to discharge. 
 
 
7.9 Contraindications to infusion of IMGN901: Because of the cytotoxic nature 
of DM1, healthy volunteers have not been exposed to IMGN901. IMGN901 is 
contraindicated in: 
 
Patients with hypersensitivity or anaphylactic reactions to IMGN901 or to 
any of the excipients. 
 
Patients who are pregnant or breast-feeding. 
 
7.10 Infusion related reactions: 
Some patients treated with IV infusions of monoclonal antibodies have 
experienced concurrent infusion-related reactions with signs or symptoms that can 


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be classified as acute allergic reactions/hypersensitivity reactions or cytokine 
release syndrome (see National Cancer Institute Common Toxicity Criteria for 
Adverse Events [NCI-CTCAE], version 4.0, Appendix F). The signs and 
symptoms include headache, fever, facial flushing, pruritus, myalgia, nausea, 
chest tightness, dyspnea, vomiting, erythema, abdominal discomfort, diaphoresis, 
shivers, hypertension, lightheadedness, hypotension, palpitations, and 
somnolence. Anaphylaxis might occur at any time during an infusion. In addition, 
the re-administration of some monoclonal antibodies has been associated with 
serum-sickness-like reactions manifesting one to 14 days after drug 
administration. 
 
The specific study protocol should be consulted regarding study drug infusions, 
the prophylactic measures that are recommended to be used for study drug 
infusions, and the management of the potential infusion/hypersensitivity 
reactions. If an anaphylactic reaction occurs, investigators are instructed that the 
infusion should be discontinued immediately and appropriate therapy initiated. 
 
7.11 Dose calculation of IMGN901 
Total dose should be calculated as in the following example: 
 
Subject’s Body Surface Area (BSA) x current dose in mg = total dose in mg 
*The dose will be rounded to the nearest multiple of 10 to avoid wastage as each 
vial contains IMGN901 100 mg 
 
For example, a subject with a BSA of 1.96 receiving a dose of 100 mg/m2 would 
be administered 200 mg of IMGN901 (1.96 x 100 mg = 196 mg: rounded to the 
nearest 10 would be 200 mg). 
 
 
8.0 PATIENT EVALUATION 
Every effort will be made to adhere to the schedule of events and all protocol 
requirements. Variations in schedule of events and other protocol 
requirements that do not affect the rights and safety of the patient will not be 
considered as deviations. Such variations may include laboratory assessments 
or follow-up visits completed outside of schedule.  
 
8.1 Pre-Treatment Evaluation 
 
Unless noted otherwise all pretreatment studies should be obtained within 
14 days from time of first dose of the study drug administration.  
 
8.1.1 
A complete history and physical, concomitant medications and 
performance status. 
 
8.1.2 
CBC, platelet count, differential (differential can be omitted if 
WBC is ≤0.5 x109/L). 


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8.1.3 
Creatinine, BUN, total bilirubin, ALT, amylase, lipase, AST, 
creatinine phosphokinase, uric acid, phosphorus, potassium, 
calcium, magnesium.  
 
8.1.4 
Pregnancy test (urine/ plasma) in females of childbearing potential, 
should be performed 72 hours (urine or plasma) before initiation of 
therapy. 
 
8.1.5 
Bone marrow aspirate within the last 28 days preceding study 
initiation. Cytogenetics will be obtained prior to therapy (results 
from prior analysis can be used for this purpose. For patients who 
already have an evidence of disease on peripheral blood or on 
tissue biopsy from another site, the bone marrow may be omitted 
after discussion and approval with the principal investigator. 
 
8.1.6 
Confirmation of CD56 expression on bone marrow, peripheral 
blood or tissue sample (e.g. lymph node sample in patients with 
BPDCN, or spleen tissue in patients with MF). 
 
8.1.7 
Baseline measurement of spleen size by palpation and/or 
ultrasound/CT for patients with myelofibrosis. 
 
8.2 Evaluation During Treatment 
 
8.2.1 
Physical exam at the start of each cycle (± 4 days). 
  
8.2.2 
CBC, platelet count, differential once weekly (4 days) for the 
first 4 cycles, then every 2-4 weeks (differential can be omitted if 
WBC is ≤0.5 x109/L).  
 
8.2.3 
Lab draw for Creatinine, BUN, sodium, potassium, uric acid, 
phosphorus, calcium, magnesium, CPK, AST pre dose on course 1 
day 1 and post dose on course 1 day 2. Creatinine, BUN, sodium, 
potassium, total bilirubin, ALT, AST, CPK, amylase, lipase 
weekly labs  (4 days) for the first 4 cycles, then every 2-4 weeks. 
 
8.2.4 
Bone marrow aspiration for differential and PCR for FLT3 on day 
21 (±7 days) of cycle 1, then every 1-3 cycles. Bone marrow tests 
can be ordered more frequently if mandated by development of 
peripheral blood counts. No repeat bone marrow is necessary if 
nonresponse or progressive disease can be unequivocally 
diagnosed from peripheral blood tests or, in patients with a WBC < 
0.3 if the bone marrow test is considered noncontributory by the 
investigator at any time point. 
 


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8.2.5 Concomitant medication data will not be collected or entered into 
the case report form except for concomitant hydroxyurea and 
intrathecal chemotherapy if these are administered during the first 
cycle; however, the subject’s medication record will contain a list 
of concomitant medications. 
 
8.2.6 
For patients that remain on study with no significant toxicity for 
more than 6 months, subsequent evaluations during study may be 
modified after discussion with the principal investigator.  These 
include a decrease in frequency of bone marrow aspirations to 
every 6-12 months (or as clinically indicated), and other laboratory 
tests to once every cycle. 
 
8.2.7 
ALL treatments with IMGN901 must be administered at MDACC. 
The patient is required to stay locally for course one. During the 
first cycle all the laboratory evaluations will be done at MDACC. 
Subsequently, the patient may have the laboratory work done at a 
local clinic and the results reported to the research nurse for the 
study. The laboratory work done at the local clinic will be 
forwarded to the patient’s attending physician at MDACC or PI of 
the study, who will sign off on the labs to verify that the results 
have been reviewed. 
 
      Outside Physician Participation During Treatment 
 
1. MDACC Physician communication with the outside physician is 
required prior to the patient returning to the local physician.  
This will be documented in the patient record 
 
2. A letter to the local physician outlining the patient's participation 
in a clinical trial will request local physician agreement to 
supervise the patient's evaluations. It will be made clear in the 
letter that all treatments with IMGN901 must be administered at 
MDACC. (Appendix E) 
 
3. Changes in drug dose and/or schedule must be discussed with 
and approved by the MDACC physician investigator, or their 
representative prior to initiation, and will be documented in the 
patient record. 
 
4. Protocol required evaluations outside MDACC will be 
documented by telephone, fax or e-mail. Fax and/or e-mail will be 
dated and signed by the MDACC physician, indicating that they 
have reviewed it.  
 
5. A copy of the informed consent, protocol abstract, treatment 


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30
schema and evaluation during treatment will be provided to the 
local physician. 
 
6. Documentation to be provided by the local physician will 
include progress notes, reports of protocol required laboratory and 
diagnostic studies and documentation of any hospitalizations. 
 
7. The home physician will be requested to report to the MDACC 
physician investigator all life threatening events within 24 hours of 
documented occurrence. 
 
8. All protocol specified follow-up visits will be performed at 
MDACC.  
 
8.2.8 
End of Treatment Visit to be completed 30 days (+/-7 days) after 
the last dose of study drug. Blood (about 2-3 teaspoons) will be 
drawn for CBC with differential and platelets and a limited 
chemistry profile (total bilirubin, serum creatinine, SGPT or 
SGOT). A bone marrow aspiration may be recommended only if 
non-response or progressive disease cannot be unequivocally 
diagnosed from peripheral blood. No other procedures or labs will 
be needed. 
 
8.2.9 
Patients with an objective response at completion of active study 
treatment will be followed for survival at MD Anderson Cancer 
Center (MDACC) every 3 to 6 months for up to 5 years after 
completion of active treatment and while still on study. If the 
patient is unable to return to MDACC the follow-up visits may be 
conducted via telephone. 
 
Data regarding adverse events will be collected during the study. Protocol specific 
data will be entered into PDMS/CORe. PDMS/CORe will be used as the 
electronic case report form for this protocol. Unexpected and related AEs will be 
recorded in the Case Report Form (CRF). All adverse events should be recorded 
on the adverse event log with attribution for review. The Principal Investigator 
will sign and date the AE log per each patient at the completion of each course. 
Following signature, the AE log will be used as source documentation for the 
adverse events for attribution.  
 
Treatment may be discontinued for a variety of reasons, including patient 
withdrawal, investigator decision, and reasons specified by the protocol. Reasons 
for discontinuation of treatments are described below. 
 
9 DISCONTINUATION OF TREATMENT: 
 
9.1 Discontinuation Criteria for Individual Patients 


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9.1.1 Patient Withdrawal 
Patients may voluntarily withdraw consent to participate in the clinical study 
at any time and without giving any reason. Their withdrawal will not 
jeopardize their relationship with their healthcare providers or affect their 
future care. Patients may also choose to withdraw from study treatment, but 
agree to remain in the study for follow-up procedures.  
 
9.1.2 Investigator Discontinuation of Patient 
The investigator may exercise medical judgment to discontinue study 
treatment if clinically significant changes in clinical status or laboratory 
values are noted. 
 
9.1.3 Criteria for Protocol-Defined Required Discontinuation of 
Treatment 
The protocol requires discontinuation of study treatment for the following 
reasons: 
1.  Patient requests discontinuation. 
2.  Unacceptable toxicity that in the opinion of the investigator makes it 
unsafe to     continue therapy.  
1. Clinically significant progressive disease.  
2. Investigator discretion. 
 
9.1.4 Follow-Up at Treatment Discontinuation or Early Withdrawal 
Patients who discontinue treatment for any reason should complete end-of-
treatment procedures when possible. End of treatment procedures will include 
a CBC with differential and platelets and a limited chemistry profile (total 
bilirubin, serum creatinine, SGPT or SGOT). A bone marrow aspiration may 
be recommended only if non-response or progressive disease cannot be 
unequivocally diagnosed from peripheral blood. Although treatment will be 
discontinued at that time, all patients who do not withdraw consent for follow-
up, die, or become lost to follow-up, will remain on study for follow-up 
evaluations. Subject will be followed for toxicity for at least 30 days after the 
last protocol treatment. The 30-day follow-up visit will be scheduled as a 
clinic visits for clinical evaluation and physical examinations. If the patient 
cannot make it to the MDACC clinic for this visit, the required follow up 
treatment procedures may be done with a local physician and the records 
forwarded to MDACC. The research nurse will contact the patient by 
telephone and get a verbal assessment of the patient’s condition. The phone 
conversation will then be documented in the patient’s charts.  
 
9.2 Study Stopping Rules 
The principal investigator and MDACC IND office have the right to terminate 
this clinical study at any time. The principal investigator and MDACC IND 
office, as appropriate, will be involved in any decisions regarding terminating the 


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study, temporarily suspending enrollment, or stopping ongoing treatment with 
study treatment. 
Reasons for terminating the clinical study or a study site’s participation include, 
but are not limited to, the following: 
 
The incidence or severity of an adverse reaction related to treatment in this 
study or other studies indicates a potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
Data recording is significantly inaccurate or incomplete 
 
Study site personnel are noncompliant with study procedures 
 
Pattern of noncompliance is observed 
 
9.3 Protocol Violations and Deviations 
Protocol violations are defined as significant departures from protocol-required 
processes or procedures that affect patient safety or benefit potential, or confound 
assessments of safety or clinical activity. A protocol deviation is a departure from 
the protocol that does not meet the above criteria. Protocol violations or 
deviations may be grouped into the following classes: 
 
Enrollment criteria 
 
Study activities 
 
Noncompliance with dose or schedule, including dose calculation, 
administration, interruption, reduction, or delay; or discontinuation criteria 
 
Investigational product handling, including storage and accountability 
 
Informed consent and ethical issues 
 
10 CRITERIA FOR RESPONSE 
Criteria for evaluation of response are specified below. The response’s will be 
determined by the treating physician on evaluation of the available data at the 
recommended time-points and will be documented in the patient notes. 
  
A. Acute leukemia, MDS and BPDCN  
Criteria for response in AML and BPDCN will be as per the international working 
group for AML.30 There are no specific criteria for response in BPDCN but since 
it is classified as an acute myeloid malignancy the AML criteria should be 
applicable. Responders are patients who obtain a Composite Complete Remission 
Rate (CRc) with or without cytogenetic response, hematologic improvements, and 
morphologic leukemia-free state. Overall response rate (ORR) is defined as the 
confirmed remission rate of all complete and incomplete CRs (i.e., CR+ CRp + 
CRi). 
 
10.1 Complete Remission (CR) 
For patients to be classified as being in CR, they must achieve a morphologic 
leukemia-free state and must have an ANC > 1 × 109/L and platelet count ≥ 100 × 
109/L, and normal marrow differential with < 5% blasts. There should be no 
evidence of extramedullary leukemia. 
 


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10.2 Complete Remission with Incomplete Platelet Recovery (CRp) 
For patients to be classified as being in CRp, they must achieve CR except for 
incomplete platelet recovery (< 100 × 109/L). 
 
10.3 Complete Remission with Incomplete Hematological Recovery (CRi) 
For patients to be classified as being in CRi, they must fulfill the criteria for CR 
except for incomplete hematological recovery with residual neutropenia (ANC ≤ 1 
× 109/L) with or without thrombocytopenia (platelet count < 100 × 109/L). In 
addition, patients do not need to be RBC or platelet transfusion independent 
(modification to Cheson criteria). 
 
10.4 Partial Remission (PR) 
For patients to be classified as being in PR, they must have bone marrow 
regenerating normal hematopoietic cells with evidence of peripheral recovery with 
no (or only a few regenerating) circulating blasts and with a decrease of at least 
50% in the percentage of blasts in the bone marrow aspirate with the total marrow 
blasts between 5% and 25%. 
 
10.5 Morphologic leukemia-free state:  
        Bone marrow: 5% myeloblasts   
 
10.7 Recurrence of Disease 
Relapse after CR is defined as a reappearance of leukemic blasts in the peripheral 
blood or ≥ 5% blasts in the bone marrow aspirate not attributable to any other cause 
or reappearance or new appearance of extramedullary leukemia. Relapse after PR is 
similarly defined with reappearance of significant numbers of peripheral blasts and 
an increase in the percentage of blasts in the bone marrow aspirate to > 25% not 
attributable to any other cause or reappearance or new appearance 
of extramedullary leukemia. 
 
10.8  Response measurement 
Response will be measured and defined for primary endpoints within 3 months of 
therapy or at time off study as the best response obtained with IMGN901 within the 
first 3 cycles of therapy. Best response is defined to be the best-measured response 
(CRc=CR+CRp+CRi, PR, or marrow clearance) post-treatment up to that time. Best 
response will also be evaluated for the full treatment period using all assessments 
up to and including treatment discontinuation. 
 
B. Myelofibrosis 
For MF refractory to ruxolitinib or JAK-inhibitor therapy, there is no standard of 
care. The efficacy of IMGN901 will be measured by the overall response rate, 
defined as a 50% shrinkage in spleen size on manual palpation (or 35% shrinkage in 
spleen size on imaging examination) and/or a 50% reduction in the total symptom 
score within 12 weeks of initiation of therapy with IMGN901. These response 
criteria are based on IWG-MRT criteria for assessment of response in 
myelofibrosis31. 


IMGN901 in hematological malignancies 
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34
 
11 ADVERSE EVENT REPORTING 
 
11.1 
Adverse event is any untoward medical occurrence that may present during 
treatment with a pharmaceutical product but which does not necessarily have 
a causal relationship with this treatment.  
 
 
Adverse drug reaction is a response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or 
therapy of disease or for the modification of physiologic function.  
 
 
Assessing causal connections between agents and disease is fundamental to 
the understanding of adverse drug reactions. In general, a drug may be 
considered a contributory cause of an adverse event if, had the drug not been 
administered, 1) the event would not have happened at all, 2) the event would 
have occurred later than it actually did, or 3) the event would have been less 
severe. 
 
 
The Investigator or physician designee is responsible for verifying and 
providing source documentation for all adverse events and assigning the 
attribution (e.g. definite, probable, possible, unlikely, unrelated) for each 
event for all subjects enrolled on the trial. 
 
11.2 
Adverse Events (AEs) will be evaluated against the most current version of 
the IMGN901 Investigator Brochure for expectedness.  The NCI CTCAE will 
be used to assess and grade AE severity. All AE assessments will be 
documented in the medical record. CTCAE version 4.0 will be used. 11.2.1 
thru 11.2.3 are exceptions from adverse event reporting:  
 
11.2.1 
Myelosuppression related events (due to disease or leukemia 
therapy) 
 
11.2.1.1 
febrile or infection episodes not requiring management in 
the intensive care unit 
 
11.2.1.2 
epistaxis or bleeding except for catastrophic CNS or 
pulmonary hemorrhage or ≥ grade 3 epistaxis or bleeding 
 
11.2.2 Disease related events 
 
11.2.2.1 
symptoms associated with anemia 
 
-fatigue 
 
-weakness 
 


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35
-shortness of breath except for grade 4 shortness of 
breath 
 
11.2.2.2 electrolyte abnormalities (sodium, potassium, 
bicarbonate, CO2, magnesium) 
 
11.2.2.3 chemistry abnormalities (LDH, phosphorus, calcium, 
BUN, protein, albumin, uric acid, alkaline phosphatase, 
glucose) 
 
11.2.2.4 coagulation abnormalities 
 
11.2.2.5 hospitalization for disease specific therapy (induction, 
maintenance, salvage, or stem cell therapy) 
 
11.2.2.6 alopecia 
 
11.2.2.7 bone,  joint, or muscle pain 
 
11.2.2.8 liver function test abnormalities associated with 
infection or disease progression 
 
11.2.2.9 disease progression 
 
11.2.2.10 abnormal hematologic values  
 
11.2.3 General therapy related events 
 
11.2.3.1 
catheter related events 
 
11.2.3.2 
rash related to antibiotic use 
 
 
11.3 
Abnormal hematologic values will not be recorded on the case report 
form.  For abnormal chemical values, the apogee or nadir (whichever is 
appropriate) will be reported per course on the case report form. 
 
11.4 
Serious Adverse Event Reporting (SAE) 
 
An adverse event (AE) is considered “serious” if, in the view of either the investigator or 
the IND Medical Monitor, it results in any of the following outcomes:  
 
 Death 
 
 A life-threatening adverse drug experience – any adverse experience 
that places the patient, in the view of the initial reporter, at immediate 


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36
risk of death from the adverse experience as it occurred. It does not 
include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
 
 Inpatient hospitalization or prolongation of existing hospitalization 
 
 A persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
 
 A congenital anomaly/birth defect. 
 
11.4.1 Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse (21 CFR 312.32). 
 
All cases of IMGN901 overdose (defined as accidental or 
intentional ingestion of any dose of the product that is considered 
excessive and medically important) must be reported as an SAE to 
the MDACC IND office on the SAE Form.  Determination of 
seriousness will be reached in consultation with the PI. 
 
Pregnancy alone is not considered an AE. However, if a patient 
becomes pregnant or causes a pregnancy during treatment or 
within 4 weeks of ending treatment, even if the subject is 
withdrawn from the study, the pregnancy must be reported 
immediately on the MD Anderson SAE Form to the MDACC IND 
office within 24 hours of the Investigator’s knowledge of the 
pregnancy.  The investigator should abide by necessary regulation 
for medical release from a female partner of a male subject prior to 
obtaining follow up.  The investigator will follow the pregnancy to 
term or termination, will collect data on both the maternal and fetal 
outcome and will report all outcomes as a follow-up report to the 
initial pregnancy notification to the MDACC IND office in 
accordance with Section 11.4.3. 
 
Notwithstanding, all pregnancy outcomes that meet the regulatory 
definition of serious (i.e. spontaneous abortion, neonatal death, 
congenital anomaly in an aborted fetus or neonate) will be reported 


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37
on the MD Anderson SAE Form to the MDACC IND office within 
24 hours of Investigator knowledge of the outcome.   
 
Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and 
should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Medical Monitor.     
 
 
All events occurring during the conduct of a protocol that 
meet the definition of a SAE must be reported to the IRB in 
accordance with the timeframes and procedures outlined in 
“University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices.” Unless stated otherwise in 
the protocol, all SAEs, expected or unexpected, must be reported 
to the MDACC IND Office, regardless of attribution (within 5 
working days of knowledge of the event). 
 
 
All life-threatening or fatal events, that are unexpected, and 
related to the study drug, must have a written report submitted 
within 24 hours (next working day) of knowledge of the event to 
the Safety Project Manager in the IND Office.   
 
 
Unless otherwise noted, the electronic SAE application 
(eSAE) will be utilized for safety reporting to the IND Office and 
MDACC IRB.  
 
 
Serious adverse events will be captured from the time of 
the first protocol-specific intervention, until 30 days after the last 
dose of drug, unless the participant withdraws consent. Serious 
adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the 
event has stabilized, or there has been acceptable resolution of the 
event. 
 
 
Additionally, any serious adverse events that occur after the 
30-day time period that is related to the study treatment must be 
reported to the MDACC IND Office. This may include the 
development of a secondary malignancy.  
 
 
Immunogen Inc. is providing the IMGN901 for this study. 
 
11.4.2 Reporting to FDA 
Serious adverse events will be forwarded to FDA by the MDACC 
IND office (Safety Project Manager IND Office) according to 21 
CFR 312.32. 


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38
 
It is the responsibility of the PI and the research team to ensure 
serious adverse events are reported according to the Code of 
Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the MDACC IND office guidelines, and Institutional 
Review Board policy. 
 
11.4.3 Investigator Communication with Supporting 
Companies 
To protect human subjects, entities that provide the IMGN901 drug 
to or receive the IMGN901 drug from other entities will share 
safety information with each other. To that end, the PI and the 
research team will provide copies of IND Safety Reports within 24 
hours of submission to ImmunoGen, Inc. Pharmacovigilance and, 
upon request, the Safety Officer of other IMGN901 entities.  In 
turn, the MD Anderson IND office (or study Principal Investigator) 
will receive IND Safety Reports originating from other entities 
using IMGN901. Each entity will provide  notification when their 
study is closed and no further safety data will be forthcoming 
 
12 STATISTICAL CONSIDERATIONS 
 
The primary objectives of the study are to evaluate the overall response rate to 
IMGN901 in patients with CD56 expressing hematological malignancies 
including but not limited to relapsed/refractory leukemia, myelofibrosis refractory 
to ruxolitinib or JAK-inhibitor therapy, and BPDCN. A response and toxicity 
summary for each treatment cohort (1, 2 and 3) will be submitted to the IND 
Medical Monitor per the guidelines found in the statistical section 12.0. 
 
Cohort 1 (Relapsed/refractory leukemia)  
The primary objective of cohort 1 is to assess the efficacy of treatment of 
IMGN901 in CD56 expressing hematological malignancies including but not 
limited to AML, high-risk MDS, natural-killer leukemia, acute lymphoblastic 
leukemia, accelerated and blast-phase CML who have failed prior therapy or for 
which no standard therapy exists. We anticipate that the majority of the patients in 
this cohort will be relapsed/refractor AML. The efficacy of IMGN901 will be 
measured by the ORR, defined as CR (complete remission) + CRp (complete 
remission with incomplete platelet recovery) + CRi (complete remission with 
incomplete count recovery) within 3 cycles of therapy with IMGN901 in patients 
with CD56 expressing leukemia’s (defined in section 10.0) who have failed prior 
therapy or for which no standard therapy exists.  
 
We anticipate that the majority of patients in this cohort will be 
relapsed/refractory AML. The historical data suggested the ORR to current 
standard salvage treatment is 30%. The target ORR with the experimental 
treatment is 50%. The regimen of the IMGN901 will be considered worthy of 


IMGN901 in hematological malignancies 
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39
further investigation if it elicits an increase in ORR to 50% with acceptable 
toxicity. A >30% therapy related non-hematological grade 3/4 toxicity rate is 
considered unacceptable.  Thus, interim monitoring rules, assuming the prior 
distributions above, were constructed that meet the following two conditions, 
1) 
Stop if   Prob[p(ORR,E) > 0.50 | data] < 0.05, or 
2) 
Stop if Prob[p(TOX,E)>0.30 | data]>0.95,  
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the 
IMGN901. The first rule provides for stopping the study if the data suggest that it 
is unlikely (i.e., probability < 5%) that ORR rate of the IMGN901 is greater than 
the ORR rate of standard treatment by 20%. The second condition will stop the 
study early if excessive therapy-related non-hematological grade 3/4 toxicity 
(>30%) is highly probable (i.e., probability >95%) for the IMGN901.  Monitoring 
for toxicity and futility will not begin until 5 patients have been evaluated, and 
cohort size for future evaluations is 5. 
The monitoring rule for the toxicity rate, based on these assumptions and 
monitoring conditions above is found in Table 4.  For example, accrual will cease 
if 4 or more patients experience toxicities among the first 5 patients. 
 
Table 4. Stop accrual if the number of drug-related non-hematological grade 3/4 
toxicities is greater than or equal to indicated (i.e., # patients with toxicities) 
among the number of patients evaluated 
# patients 
evaluated  
5 
10 
15 
20 
# patients with 
toxicities 
4-5 
6-
10 
8-
15 
Always stop 
with this many 
patients 
 
Monitoring the ORR rate, based on the above assumptions and monitoring 
conditions is found in Table 5.  For example, accrual will cease if less than 1 
patient experience an overall response within 3 cycles of IMGN901 in the first 15 
patients treated. If <1/15 of the initially treated patients achieve response we will 
consider alternate dosing schedule with IMGN901 administered on days 1,8,15 of 
a 21-day cycle. This will be done in discussion with the MDACC IND office, 
FDA and the IRB. Rules for dose-interruption and dose-adjustment will remain as 
defined in the protocol. 
 
 
Table 5. Stop accrual if the number with overall response is 
less than or equal to indicated (i.e., # patients with overall 
response) among the number of patients evaluated 
# patients 
evaluated 
5 
10 
15 
20 
# patients 
with 
 overall 
response 
0 
0-2 
0-4 
Always stop 
with  
this many 
patients 
 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
40
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility 
stopping boundaries and the OC table (Table 6). In order to utilize the software 
for the design, a response constant rate of 0.30 and beta (0.6, 1.4) priors and delta 
of 20% were assumed for the standard treatment response distribution and 
experimental treatment response prior distribution, respectively. In addition, a 
30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the standard 
treatment toxicity constant rate and experimental treatment toxicity prior 
distribution, respectively. 
 
The probability of stopping the study early if the true ORR of the IMGN901 was 
50% and the true toxicity rate was 30% was 11.3%. Probabilities of stopping early 
for high true toxicity rates (i.e., 50%) were 63.7% when the true ORR was 30% 
and 57.3% when true ORR rate was 50%. 
 
Table 6.  Operating characteristics for simultaneous monitoring response and 
toxicity rates for patients treated with IMGN901 treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.30 
0.5725 
 
0.40 
0.2778 
 
0.50 
0.0972 
 
0.60 
0.0244 
 
0.70 
0.0045 
0.20 
0.30 
0.5779 
 
0.40 
0.2870 
 
0.50 
0.1086 
 
0.60 
0.0367 
 
0.70 
0.0171 
0.30 
0.30 
0.6083 
 
0.40 
0.3384 
 
0.50 
0.1730 
 
0.60 
0.1062 
 
0.70 
0.0881 
0.40 
0.30 
0.6892 
 
0.40 
0.4751 
 
0.50 
0.3438 
 
0.60 
0.2908 
 
0.70 
0.2764 
0.50 
0.30 
0.8113 
 
0.40 
0.6812 
 
0.50 
0.6014 
 
0.60 
0.5693 
 
0.70 
0.5605 
 
 
Cohort 2 (Myelofibrosis refractory to JAK-inhibitor therapy) 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
41
The primary objective of the cohort 2 is to assess the efficacy of IMGN901 in MF 
patients who are refractory to JAK-inhibitor therapy. No standard of care exists 
for such patients. The efficacy of  IMGN901 will be measured by the overall 
response rate, defined as a 50% shrinkage in spleen size on manual palpation (or 
35% shrinkage in spleen size on imaging examination) and/or a 50% reduction in 
the total symptom score within 3 cycles of IMGN901 therapy.  
 
Futility Monitoring 
 
Historical data on similar patients shows an ORR of 20%. The target response rate 
is 35%. Given this, we will stop enrollment into this cohort if the observed 
patients’ data suggest that: 
 
Pr (p(ORR, E) > 0.35|data) < 0.025 
where P(ORR, E) s the overall response rate (ORR) for the treatment. That is, if at 
any time during the study we determine that there is a less than 2.5% chance that 
ORR rate of the IMGN901 is greater than the ORR rate of standard treatment by 
15% we will stop enrollment to this cohort. P(ORR, E) is assumed to follow a 
prior of Beta (0.4, 1.6). The stopping boundaries for ORR, based on these 
assumptions and monitoring conditions are found in Table 7. We will apply these 
stopping boundaries continuously starting from the first patient in cohorts of 10. 
For example, accrual will cease if 0 patients experiences overall response among 
the first 10 patients treated within 3 cycles of therapy with IMGN901. The 
operating characteristics are summarized in Table 8. 
 
Table 7. Stopping boundaries for ORR 
 
Number of patients evaluated for overall response 
10 
20 
Number of patients with overall response  
(i.e., CR, CRp  or CRi) is less than or equal to 
0 – 1  
2-4 
 
Table 8. Operating characteristics for monitoring ORR 
True 
overall 
Response 
Rate 
Early Stopping 
Probability 
Average number of 
patients treated 
0.20 
0.3758 
16 
0.25 
0.2440 
18 
0.30 
0.1493 
19 
0.35 
0.0860 
19 
0.40 
0.0464 
20 
0.45 
0.0233 
20 
 
 
Toxicity Monitoring  


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
42
In addition, we will monitor toxicities. The probability of toxicity is denoted by 
P(TOX, E). We assume P(TOX, E)  ~ beta (0.6, 1.4).  Our stopping rule is given 
by the following probability statement: Pr(P(TOX, E) > 0.30 | data)>0.85. That is, 
we will stop the study if, at any time during the study, we determine that there is 
more than 90% chance that the toxicity is more than 30%. The stopping 
boundaries for toxicities, based on these assumptions and monitoring conditions is 
found in Table 9. We will apply the toxicity monitoring rule in cohort size of 5, 
starting from the 1st patient. For example, accrual will cease if all 3 patients 
experience toxicities among the first 5 patients treated. The operating 
characteristics are summarized in Table 10. 
 
Table 9. Stopping boundaries for toxicity monitoring  
 
The number  of patients evaluated 
for toxicities 
5 
10 
15 
20 
The number  of patients with 
toxicities is greater than or equal 
to  
3 
5 
7 
9 
 
Table 10. Operating characteristics for toxicity monitoring 
True 
overall 
Toxicity 
Rate 
Early Stopping 
Probability 
Average number of patients 
treated 
0.10 
0.0089 
20 
0.20 
0.0787 
19 
0.30 
0.2607 
17 
0.40 
0.5173 
14 
0.50 
0.7846 
10 
 
 
Cohort 3 (BPDCN) 
The primary objective of the cohort 3 is to assess the efficacy of IMGN901 in 
patients with a confirmed pathological diagnosis of BPDCN. The efficacy of 
IMGN901 will be measured by the ORR, defined as CR (complete remission) + 
CRp (complete remission with incomplete platelet recovery) + CRi (complete 
remission with incomplete count recovery) (as specified in section 10.0) within 3 
cycles of therapy with IMGN901.  
 
Futility Monitoring 
Historical data on similar patients show a ORR of 20%. The target response rate 
is 35%. Given this, we will stop enrollment into this cohort if the observed 
patients’ data suggest that: 
 
Pr (p(TOX,E)> 0.35|data) < 0.025 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
43
 
where p(ORR,E) is the overall response rate (ORR) for the treatment. That is, if at 
any time during the study we determine that there is a less than 2.5% chance that 
ORR rate of the IMGN901 is greater than the ORR rate of standard treatment by 
15% we will stop enrollment to this cohort. P(ORR,E) is assumed to follow a 
prior of Beta (0.4, 1.6). The stopping boundaries for ORR, based on these 
assumptions and monitoring conditions are found in Table 11. We will apply 
these stopping boundaries continuously starting from the first patient and in 
cohorts of 10.  For example, accrual will cease if less than 1 patients experiences 
overall response among the first 10 patients treated within 3 cycles of therapy 
with IMGN901. The operating characteristics are summarized in Table 12. 
 
Table 11. Stopping boundaries for ORR 
 
Number of patients evaluated for overall response 
10 
20 
Number of patients with overall response  
(i.e., CR, CRp  or CRi) is less than or equal to 
0-1 
2-4 
 
Table 12. Operating characteristics for monitoring ORR 
True 
overall 
Response 
Rate 
Early Stopping 
Probability 
Average number of 
patients treated 
0.20 
0.3758 
16 
0.25 
0.2440 
18 
0.30 
0.1493 
19 
0.35 
0.0860 
19 
0.40 
0.0464 
20 
0.45 
0.0233 
20 
 
 
Toxicity Monitoring  
In addition, we will monitor toxicities. The probability of toxicity is denoted by 
P(TOX, E). We assume P(TOX, E) ~ beta (0.6, 1.4). Our stopping rule is given by 
the following probability statement: Pr(P(TOX, E) > 0.30 | data)>0.85. That is, we 
will stop the study if, at any time during the study, we determine that there is 
more than 90% chance that the toxicity is more than 30%. The stopping 
boundaries for toxicities, based on these assumptions and monitoring conditions is 
found in Table 13. We will apply the toxicity monitoring rule in cohort size of 5, 
starting from the 1st patient. For example, accrual will cease if all 3 patients 
experience toxicities among the first 5 patients treated. The operating 
characteristics are summarized in Table 14. 
 
Table 13. Stopping boundaries for toxicity monitoring  
 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
44
The number  of patients evaluated 
for toxicities 
5 
10 
15 
20 
The number  of patients with 
toxicities is greater than or equal 
to  
3 
5 
7 
9 
 
Table 14. Operating characteristics for toxicity monitoring 
True 
overall 
Toxicity 
Rate 
Early Stopping 
Probability 
Average number of patients 
treated 
0.10 
0.0089 
20 
0.20 
0.0787 
19 
0.30 
0.2607 
17 
0.40 
0.5173 
14 
0.50 
0.7846 
10 
 
 
 
Statistical Analysis Plan 
 
All patients who received any dose of the study agent will be included in the 
analysis for efficacy and safety.  Demographic/clinical characteristics (including 
duration of response) and safety data of the patients will be summarized using 
descriptive statistics such as mean, standard deviation, median and range. For the 
primary efficacy analysis, we will estimate the ORR for the IMGN901, along with 
the 95% confidence interval. Patients who drop out of the study before 
completing all the cycles will be treated as “failures” for the primary analysis. 
Overall response rate (ORR) during the study period will also be presented with 
the 95% confidence interval. The association between ORR and patient’s clinical 
characteristics will be examined by Wilcoxon’s rank sum test or Fisher’s exact 
test, as appropriate. Toxicity type, severity and attribution will be summarized for 
each patient using frequency tables.  The distribution of time-to-event endpoints 
including  duration of response,   overall survival and progression free survival 
will be estimated using the method of Kaplan and Meier. Comparisons of time-to-
event endpoints by important subgroups will be made using the log-rank tests. 
Correlation analysis (such as logistic regression analysis) will be conducted to 
determine the relationship between IMGN901 and other gene expression and 
clinical response.    
 
 
13.0 REFERENCES: 
 
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63: 
11-30. 


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7/16/2015 
 
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2. Heerema-McKenney A, Arber DA. Acute myeloid leukemia. Hematol Oncol Clin 
North Am. 2009;23: 633-654. 
3. Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. 
Blood. 2006;107: 3481-3485. 
4. Kantarjian HM. Therapy for elderly patients with acute myeloid leukemia: a problem 
in search of solutions. Cancer. 2007;109: 1007-1010. 
5. Kantarjian H, O'Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 
patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic 
syndrome: predictive prognostic models for outcome. Cancer. 2006;106: 1090-1098. 
6. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. 
Leukemia. 2000;14: 476-479. 
7. Ravandi F, Cortes J, Faderl S, et al. Characteristics and outcome of patients with acute 
myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction 
chemotherapy. Blood. 2010;116: 5818-5823; quiz 6153. 
8. Stanisic S, Kalaycio M. Treatment of refractory and relapsed acute myelogenous 
leukemia. Expert Rev Anticancer Ther. 2002;2: 287-295. 
9. Seymour JF, Pierce SA, Kantarjian HM, Keating MJ, Estey EH. Investigation of 
karyotypic, morphologic and clinical features in patients with acute myeloid leukemia 
blast cells expressing the neural cell adhesion molecule (CD56). Leukemia. 1994;8: 823-
826. 
10. Mann KP, DeCastro CM, Liu J, Moore JO, Bigner SH, Traweek ST. Neural cell 
adhesion molecule (CD56)-positive acute myelogenous leukemia and myelodysplastic 
and myeloproliferative syndromes. Am J Clin Pathol. 1997;107: 653-660. 
11. Legrand O, Perrot JY, Baudard M, et al. The immunophenotype of 177 adults with 
acute myeloid leukemia: proposal of a prognostic score. Blood. 2000;96: 870-877. 
12. Chang H, Brandwein J, Yi QL, Chun K, Patterson B, Brien B. Extramedullary 
infiltrates of AML are associated with CD56 expression, 11q23 abnormalities and 
inferior clinical outcome. Leuk Res. 2004;28: 1007-1011. 
13. Junca J, Garcia-Caro M, Granada I, et al. Correlation of CD11b and CD56 expression 
in adult acute myeloid leukemia with cytogenetic risk groups and prognosis. Ann 
Hematol. 2014;93: 1483-1489. 
14. Di Bona E, Sartori R, Zambello R, Guercini N, Madeo D, Rodeghiero F. Prognostic 
significance of CD56 antigen expression in acute myeloid leukemia. Haematologica. 
2002;87: 250-256. 
15. Baer MR, Stewart CC, Lawrence D, et al. Expression of the neural cell adhesion 
molecule CD56 is associated with short remission duration and survival in acute myeloid 
leukemia with t(8;21)(q22;q22). Blood. 1997;90: 1643-1648. 
16. Yang DH, Lee JJ, Mun YC, et al. Predictable prognostic factor of CD56 expression in 
patients with acute myeloid leukemia with t(8 : 21) after high dose cytarabine or 
allogeneic hematopoietic stem cell transplantation. Am J Hematol. 2007;82: 1-5. 
17. Murray CK, Estey E, Paietta E, et al. CD56 expression in acute promyelocytic 
leukemia: a possible indicator of poor treatment outcome? J Clin Oncol. 1999;17: 293-
297. 
18. Raspadori D, Damiani D, Lenoci M, et al. CD56 antigenic expression in acute 
myeloid leukemia identifies patients with poor clinical prognosis. Leukemia. 2001;15: 
1161-1164. 


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7/16/2015 
 
46
19. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms 
in the United States. Leuk Lymphoma. 2014;55: 595-600. 
20. Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic 
International Prognostic Scoring System for primary myelofibrosis that incorporates 
prognostic information from karyotype, platelet count, and transfusion status. J Clin 
Oncol. 2011;29: 392-397. 
21. Mesa RA, Mehta J, Wang HW, et al. Epidemiology of Myeloproliferative Disorders 
in US - a Real World Analysis. Blood. 2012;120. 
22. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of 
ruxolitinib for myelofibrosis. N Engl J Med. 2012;366: 799-807. 
23. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best 
available therapy for myelofibrosis. N Engl J Med. 2012;366: 787-798. 
24. Feng B, Verstovsek S, Jorgensen JL, Lin P. Aberrant myeloid maturation identified 
by flow cytometry in primary myelofibrosis. Am J Clin Pathol. 2010;133: 314-320. 
25. Cota C, Vale E, Viana I, et al. Cutaneous manifestations of blastic plasmacytoid 
dendritic cell neoplasm-morphologic and phenotypic variability in a series of 33 patients. 
Am J Surg Pathol. 2010;34: 75-87. 
26. Petrella T, Bagot M, Willemze R, et al. Blastic NK-cell lymphomas (agranular 
CD4+CD56+ hematodermic neoplasms): a review. Am J Clin Pathol. 2005;123: 662-675. 
27. Woll PJ, O'Brien M, Fossella F, et al. Phase I Study of Lorvotuzumab Mertansine 
(Imgn901) in Patients with Cd56-Positive Solid Tumours. Annals of Oncology. 2010;21: 
175-176. 
28. Chanan-Khan A, Wolf JL, Garcia J, et al. Efficacy Analysis From Phase I Study of 
Lorvotuzumab Mertansine (IMGN901), Used as Monotherapy, In Patients with Heavily 
Pre-Treated CD56-Positive Multiple Myeloma - A Preliminary Efficacy Analysis. Blood. 
2010;116: 819-819. 
29. Berdeja JG, Hernandez-Ilizaliturri F, Chanan-Khan A, et al. Phase I Study of 
Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Lenalidomide (Len) 
and Dexamethasone (Dex) in Patients with CD56-Positive Relapsed or 
Relapsed/Refractory Multiple Myeloma (MM). Blood. 2012;120. 
30. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J Clin Oncol. 2003;21: 4642-4649. 
31. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: 
International Working Group-Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122: 
1395-1398. 
 
 

SAP_001.pdf: 
IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
38
 
It is the responsibility of the PI and the research team to ensure 
serious adverse events are reported according to the Code of 
Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the MDACC IND office guidelines, and Institutional 
Review Board policy. 
 
11.4.3 Investigator Communication with Supporting 
Companies 
To protect human subjects, entities that provide the IMGN901 drug 
to or receive the IMGN901 drug from other entities will share 
safety information with each other. To that end, the PI and the 
research team will provide copies of IND Safety Reports within 24 
hours of submission to ImmunoGen, Inc. Pharmacovigilance and, 
upon request, the Safety Officer of other IMGN901 entities.  In 
turn, the MD Anderson IND office (or study Principal Investigator) 
will receive IND Safety Reports originating from other entities 
using IMGN901. Each entity will provide  notification when their 
study is closed and no further safety data will be forthcoming 
 
12 STATISTICAL CONSIDERATIONS 
 
The primary objectives of the study are to evaluate the overall response rate to 
IMGN901 in patients with CD56 expressing hematological malignancies 
including but not limited to relapsed/refractory leukemia, myelofibrosis refractory 
to ruxolitinib or JAK-inhibitor therapy, and BPDCN. A response and toxicity 
summary for each treatment cohort (1, 2 and 3) will be submitted to the IND 
Medical Monitor per the guidelines found in the statistical section 12.0. 
 
Cohort 1 (Relapsed/refractory leukemia)  
The primary objective of cohort 1 is to assess the efficacy of treatment of 
IMGN901 in CD56 expressing hematological malignancies including but not 
limited to AML, high-risk MDS, natural-killer leukemia, acute lymphoblastic 
leukemia, accelerated and blast-phase CML who have failed prior therapy or for 
which no standard therapy exists. We anticipate that the majority of the patients in 
this cohort will be relapsed/refractor AML. The efficacy of IMGN901 will be 
measured by the ORR, defined as CR (complete remission) + CRp (complete 
remission with incomplete platelet recovery) + CRi (complete remission with 
incomplete count recovery) within 3 cycles of therapy with IMGN901 in patients 
with CD56 expressing leukemia’s (defined in section 10.0) who have failed prior 
therapy or for which no standard therapy exists.  
 
We anticipate that the majority of patients in this cohort will be 
relapsed/refractory AML. The historical data suggested the ORR to current 
standard salvage treatment is 30%. The target ORR with the experimental 
treatment is 50%. The regimen of the IMGN901 will be considered worthy of 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
39
further investigation if it elicits an increase in ORR to 50% with acceptable 
toxicity. A >30% therapy related non-hematological grade 3/4 toxicity rate is 
considered unacceptable.  Thus, interim monitoring rules, assuming the prior 
distributions above, were constructed that meet the following two conditions, 
1) 
Stop if   Prob[p(ORR,E) > 0.50 | data] < 0.05, or 
2) 
Stop if Prob[p(TOX,E)>0.30 | data]>0.95,  
where P(ORR, E) and P(TOX, E) are the true ORR and toxicity rates for the 
IMGN901. The first rule provides for stopping the study if the data suggest that it 
is unlikely (i.e., probability < 5%) that ORR rate of the IMGN901 is greater than 
the ORR rate of standard treatment by 20%. The second condition will stop the 
study early if excessive therapy-related non-hematological grade 3/4 toxicity 
(>30%) is highly probable (i.e., probability >95%) for the IMGN901.  Monitoring 
for toxicity and futility will not begin until 5 patients have been evaluated, and 
cohort size for future evaluations is 5. 
The monitoring rule for the toxicity rate, based on these assumptions and 
monitoring conditions above is found in Table 4.  For example, accrual will cease 
if 4 or more patients experience toxicities among the first 5 patients. 
 
Table 4. Stop accrual if the number of drug-related non-hematological grade 3/4 
toxicities is greater than or equal to indicated (i.e., # patients with toxicities) 
among the number of patients evaluated 
# patients 
evaluated  
5 
10 
15 
20 
# patients with 
toxicities 
4-5 
6-
10 
8-
15 
Always stop 
with this many 
patients 
 
Monitoring the ORR rate, based on the above assumptions and monitoring 
conditions is found in Table 5.  For example, accrual will cease if less than 1 
patient experience an overall response within 3 cycles of IMGN901 in the first 15 
patients treated. If <1/15 of the initially treated patients achieve response we will 
consider alternate dosing schedule with IMGN901 administered on days 1,8,15 of 
a 21-day cycle. This will be done in discussion with the MDACC IND office, 
FDA and the IRB. Rules for dose-interruption and dose-adjustment will remain as 
defined in the protocol. 
 
 
Table 5. Stop accrual if the number with overall response is 
less than or equal to indicated (i.e., # patients with overall 
response) among the number of patients evaluated 
# patients 
evaluated 
5 
10 
15 
20 
# patients 
with 
 overall 
response 
0 
0-2 
0-4 
Always stop 
with  
this many 
patients 
 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
40
Multc Lean Desktop (version 2.1.0) was used to generate the toxicity and futility 
stopping boundaries and the OC table (Table 6). In order to utilize the software 
for the design, a response constant rate of 0.30 and beta (0.6, 1.4) priors and delta 
of 20% were assumed for the standard treatment response distribution and 
experimental treatment response prior distribution, respectively. In addition, a 
30% toxicity constant rate and beta (0.6, 1.4) priors were assumed for the standard 
treatment toxicity constant rate and experimental treatment toxicity prior 
distribution, respectively. 
 
The probability of stopping the study early if the true ORR of the IMGN901 was 
50% and the true toxicity rate was 30% was 11.3%. Probabilities of stopping early 
for high true toxicity rates (i.e., 50%) were 63.7% when the true ORR was 30% 
and 57.3% when true ORR rate was 50%. 
 
Table 6.  Operating characteristics for simultaneous monitoring response and 
toxicity rates for patients treated with IMGN901 treatment 
True Toxicity Rate 
True ORR 
Prob(stop the trial early) 
0.10 
0.30 
0.5725 
 
0.40 
0.2778 
 
0.50 
0.0972 
 
0.60 
0.0244 
 
0.70 
0.0045 
0.20 
0.30 
0.5779 
 
0.40 
0.2870 
 
0.50 
0.1086 
 
0.60 
0.0367 
 
0.70 
0.0171 
0.30 
0.30 
0.6083 
 
0.40 
0.3384 
 
0.50 
0.1730 
 
0.60 
0.1062 
 
0.70 
0.0881 
0.40 
0.30 
0.6892 
 
0.40 
0.4751 
 
0.50 
0.3438 
 
0.60 
0.2908 
 
0.70 
0.2764 
0.50 
0.30 
0.8113 
 
0.40 
0.6812 
 
0.50 
0.6014 
 
0.60 
0.5693 
 
0.70 
0.5605 
 
 
Cohort 2 (Myelofibrosis refractory to JAK-inhibitor therapy) 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
41
The primary objective of the cohort 2 is to assess the efficacy of IMGN901 in MF 
patients who are refractory to JAK-inhibitor therapy. No standard of care exists 
for such patients. The efficacy of  IMGN901 will be measured by the overall 
response rate, defined as a 50% shrinkage in spleen size on manual palpation (or 
35% shrinkage in spleen size on imaging examination) and/or a 50% reduction in 
the total symptom score within 3 cycles of IMGN901 therapy.  
 
Futility Monitoring 
 
Historical data on similar patients shows an ORR of 20%. The target response rate 
is 35%. Given this, we will stop enrollment into this cohort if the observed 
patients’ data suggest that: 
 
Pr (p(ORR, E) > 0.35|data) < 0.025 
where P(ORR, E) s the overall response rate (ORR) for the treatment. That is, if at 
any time during the study we determine that there is a less than 2.5% chance that 
ORR rate of the IMGN901 is greater than the ORR rate of standard treatment by 
15% we will stop enrollment to this cohort. P(ORR, E) is assumed to follow a 
prior of Beta (0.4, 1.6). The stopping boundaries for ORR, based on these 
assumptions and monitoring conditions are found in Table 7. We will apply these 
stopping boundaries continuously starting from the first patient in cohorts of 10. 
For example, accrual will cease if 0 patients experiences overall response among 
the first 10 patients treated within 3 cycles of therapy with IMGN901. The 
operating characteristics are summarized in Table 8. 
 
Table 7. Stopping boundaries for ORR 
 
Number of patients evaluated for overall response 
10 
20 
Number of patients with overall response  
(i.e., CR, CRp  or CRi) is less than or equal to 
0 – 1  
2-4 
 
Table 8. Operating characteristics for monitoring ORR 
True 
overall 
Response 
Rate 
Early Stopping 
Probability 
Average number of 
patients treated 
0.20 
0.3758 
16 
0.25 
0.2440 
18 
0.30 
0.1493 
19 
0.35 
0.0860 
19 
0.40 
0.0464 
20 
0.45 
0.0233 
20 
 
 
Toxicity Monitoring  


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
42
In addition, we will monitor toxicities. The probability of toxicity is denoted by 
P(TOX, E). We assume P(TOX, E)  ~ beta (0.6, 1.4).  Our stopping rule is given 
by the following probability statement: Pr(P(TOX, E) > 0.30 | data)>0.85. That is, 
we will stop the study if, at any time during the study, we determine that there is 
more than 90% chance that the toxicity is more than 30%. The stopping 
boundaries for toxicities, based on these assumptions and monitoring conditions is 
found in Table 9. We will apply the toxicity monitoring rule in cohort size of 5, 
starting from the 1st patient. For example, accrual will cease if all 3 patients 
experience toxicities among the first 5 patients treated. The operating 
characteristics are summarized in Table 10. 
 
Table 9. Stopping boundaries for toxicity monitoring  
 
The number  of patients evaluated 
for toxicities 
5 
10 
15 
20 
The number  of patients with 
toxicities is greater than or equal 
to  
3 
5 
7 
9 
 
Table 10. Operating characteristics for toxicity monitoring 
True 
overall 
Toxicity 
Rate 
Early Stopping 
Probability 
Average number of patients 
treated 
0.10 
0.0089 
20 
0.20 
0.0787 
19 
0.30 
0.2607 
17 
0.40 
0.5173 
14 
0.50 
0.7846 
10 
 
 
Cohort 3 (BPDCN) 
The primary objective of the cohort 3 is to assess the efficacy of IMGN901 in 
patients with a confirmed pathological diagnosis of BPDCN. The efficacy of 
IMGN901 will be measured by the ORR, defined as CR (complete remission) + 
CRp (complete remission with incomplete platelet recovery) + CRi (complete 
remission with incomplete count recovery) (as specified in section 10.0) within 3 
cycles of therapy with IMGN901.  
 
Futility Monitoring 
Historical data on similar patients show a ORR of 20%. The target response rate 
is 35%. Given this, we will stop enrollment into this cohort if the observed 
patients’ data suggest that: 
 
Pr (p(TOX,E)> 0.35|data) < 0.025 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
43
 
where p(ORR,E) is the overall response rate (ORR) for the treatment. That is, if at 
any time during the study we determine that there is a less than 2.5% chance that 
ORR rate of the IMGN901 is greater than the ORR rate of standard treatment by 
15% we will stop enrollment to this cohort. P(ORR,E) is assumed to follow a 
prior of Beta (0.4, 1.6). The stopping boundaries for ORR, based on these 
assumptions and monitoring conditions are found in Table 11. We will apply 
these stopping boundaries continuously starting from the first patient and in 
cohorts of 10.  For example, accrual will cease if less than 1 patients experiences 
overall response among the first 10 patients treated within 3 cycles of therapy 
with IMGN901. The operating characteristics are summarized in Table 12. 
 
Table 11. Stopping boundaries for ORR 
 
Number of patients evaluated for overall response 
10 
20 
Number of patients with overall response  
(i.e., CR, CRp  or CRi) is less than or equal to 
0-1 
2-4 
 
Table 12. Operating characteristics for monitoring ORR 
True 
overall 
Response 
Rate 
Early Stopping 
Probability 
Average number of 
patients treated 
0.20 
0.3758 
16 
0.25 
0.2440 
18 
0.30 
0.1493 
19 
0.35 
0.0860 
19 
0.40 
0.0464 
20 
0.45 
0.0233 
20 
 
 
Toxicity Monitoring  
In addition, we will monitor toxicities. The probability of toxicity is denoted by 
P(TOX, E). We assume P(TOX, E) ~ beta (0.6, 1.4). Our stopping rule is given by 
the following probability statement: Pr(P(TOX, E) > 0.30 | data)>0.85. That is, we 
will stop the study if, at any time during the study, we determine that there is 
more than 90% chance that the toxicity is more than 30%. The stopping 
boundaries for toxicities, based on these assumptions and monitoring conditions is 
found in Table 13. We will apply the toxicity monitoring rule in cohort size of 5, 
starting from the 1st patient. For example, accrual will cease if all 3 patients 
experience toxicities among the first 5 patients treated. The operating 
characteristics are summarized in Table 14. 
 
Table 13. Stopping boundaries for toxicity monitoring  
 


IMGN901 in hematological malignancies 
Protocol #2014-0926 
7/16/2015 
 
44
The number  of patients evaluated 
for toxicities 
5 
10 
15 
20 
The number  of patients with 
toxicities is greater than or equal 
to  
3 
5 
7 
9 
 
Table 14. Operating characteristics for toxicity monitoring 
True 
overall 
Toxicity 
Rate 
Early Stopping 
Probability 
Average number of patients 
treated 
0.10 
0.0089 
20 
0.20 
0.0787 
19 
0.30 
0.2607 
17 
0.40 
0.5173 
14 
0.50 
0.7846 
10 
 
 
 
Statistical Analysis Plan 
 
All patients who received any dose of the study agent will be included in the 
analysis for efficacy and safety.  Demographic/clinical characteristics (including 
duration of response) and safety data of the patients will be summarized using 
descriptive statistics such as mean, standard deviation, median and range. For the 
primary efficacy analysis, we will estimate the ORR for the IMGN901, along with 
the 95% confidence interval. Patients who drop out of the study before 
completing all the cycles will be treated as “failures” for the primary analysis. 
Overall response rate (ORR) during the study period will also be presented with 
the 95% confidence interval. The association between ORR and patient’s clinical 
characteristics will be examined by Wilcoxon’s rank sum test or Fisher’s exact 
test, as appropriate. Toxicity type, severity and attribution will be summarized for 
each patient using frequency tables.  The distribution of time-to-event endpoints 
including  duration of response,   overall survival and progression free survival 
will be estimated using the method of Kaplan and Meier. Comparisons of time-to-
event endpoints by important subgroups will be made using the log-rank tests. 
Correlation analysis (such as logistic regression analysis) will be conducted to 
determine the relationship between IMGN901 and other gene expression and 
clinical response.    
 
 
13.0 REFERENCES: 
 
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63: 
11-30.