Conditions: AML
Keywords: AML
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
This research study is evaluating how a drug called lenalidomide, given in combination with the standard chemotherapy regimen of Mitoxantrone, Etoposide, and Cytarabine, commonly referred to as MEC, works in individuals with either relapsed or refractory AML

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved lenalidomide for this specific disease, but it has been approved for other uses, including for patients with multiple myeloma and some patients with myelodysplastic syndrome. This treatment is investigational because it is not approved by the FDA for patients with AML. Lenalidomide is a chemotherapy that also modulates the immune system, and is in a category of drugs called immunomodulatory drugs or IMIDs. Some research studies suggest that lenalidomide may be effective in patients with AML. Since the investigators know that many patients who receive MEC chemotherapy alone have less than desired response rates and overall shorter periods of remission (time free from leukemia) after treatment, the investigators are studying whether the addition of lenalidomide to MEC improves upon typical responses.

The combination of MEC (mitoxantrone, etoposide, and cytarabine) is a standard treatment option, commonly used for relapsed or refractory acute myeloid leukemia.

.

Arms:
arm 1: Lenalidomide is taken orally on a daily basis days 1-10. Mitoxantrone, Etoposide, and Cytarabine are administered intravenously on a daily basis for days 4 through 8 of the treatment. There is only one cycle of treatment in this study.

Interventions: intervention 1: Etoposide intervention 2: Cytarabine intervention 3: Lenalidomide intervention 4: Mitoxantrone
Intervention descriptions: intervention 1: A Drug that interfere with the action of topoisomerase enzymes (topoisomerase I and II). Topoisomerase enzymes control the manipulation of the structure of DNA necessary for replication. intervention 2: Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. intervention 3: It may act by inhibiting the growth of new blood vessels (angiogenesis) in tumors, enhancing the status of the immune system, or decreasing cytokine and growth factor production intervention 4: It interfere with cell reproduction

Protocol document:
Prot_SAP_000.pdf: 




DF/HCC Protocol #: 16-574 
Protocol Version Date: 2/27/19 
 
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SYNOPSIS AND SCHEMA 
 
Title: 
 
Phase 2 Study of Mitoxantrone, Etoposide, and Cytarabine (MEC) plus Lenalidomide for the 
treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) 
 
Primary Objective:  
 
The primary objective of this study is to assess rates of complete remission (CR) and rates of 
complete remission with incomplete platelet recovery (CRp) after treatment with mitoxantrone, 
etoposide, cytarabine (MEC) and lenalidomide. 
 
Secondary Objectives: 
 
1.   To evaluate the days to neutrophil recovery (the first of 3 days of ANC >500). 
 
2.   To evaluate the days to platelet recovery (platelet count >20K unsupported). 
3.   To evaluate the treatment-related mortality (the number of non-relapse related deaths in the first 50 
days of starting treatment.) 
4.   To evaluate the transfusion support (the number of red blood cell and platelet transfusions 
needed in the first 50 days of treatment). 
5.   To determine if certain genetic profiles of the leukemia predict for better response (optional 
correlative study)  
6.    To evaluate relapse and survival following treatment with MEC and lenalidomide. 
 
Study Design: 
 
This is a single arm Phase 2 study which consists of determining the overall response rate of 
Lenalidomide + MEC in relapsed or refractory AML patients.  A 45% complete remission rate 
will be considered clinically significant.  
 
Simon’s two stage optimal design is used to compute the sample size.  A total number of 40 
patients is needed in order to detect a 20% CR rate increase assuming the CR for null hypothesis 
is 25% with a 90% power and 9% type I error.  The study will be reevaluated if 4 or fewer 
responses out of 18 patients are observed and the study will be declared inactive if fewer than 14 
responses are seen in the total 40 patients.  The probability of stopping at the first stage is 0.52.  
 
Accrual Objective: 40 - 42 patients in order to enroll 40 evaluable patients. 
 
Accrual Period: The estimated accrual period is 2.5 years 
 
Eligibility Criteria: 
 
The following criteria must be met prior to enrolling. 
• Acute myelogenous leukemia diagnosed by WHO criteria with one of the following: 
- 
Primary refractory disease following > 1 cycle of induction chemotherapy. 


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- 
First relapse or higher. Patients with primary or secondary acute myelogenous 
leukemia are eligible. Patients with biphenotypic leukemia are eligible. 
• 18-70 years 
• LVEF > 50% 
• ECOG Performance status 0-2 
• Creatinine <2.0 mg/dl and eGFR ≥ 60 mL/min. 
• Total bilirubin < 1.5 x institutional ULN 
• AST (SGOT) and ALT (SGPT) ≤ 3 x institutionalULN 
• Able to adhere to study schedule and other protocol requirements 
• Patients may receive hydroxyurea, steroids, or leukapheresis as necessary until Day 5 of 
treatment. 
 
Treatment Description: 
 
Patients will receive only one cycle of treatment, as below: 
1.  Lenalidomide Days 1-10 
2.  Mitoxantrone by IV infusion over approximately 6-10 minutes for 5 days (days 4-8) 
3.  Etoposide IV over approximately 1 hour daily for 5 days (days 4-8) 
4.  Cytarabine IV over approximately 1 hour daily for 5 days (days 4-8). 
  
 
Table 1: Schema for reinduction chemotherapy treatment 
 
 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Mitoxantrone 
(intravenous) 
 
 
 
X 
X 
X 
X 
X 
 
 
Etoposide 
(intravenous) 
 
 
 
X 
X 
X 
X 
X 
 
 
Cytarabine 
(intravenous) 
 
 
 
X 
X 
X 
X 
X 
 
 
Lenalidomide 
(oral) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Duration:  
Participants will be followed for at least 50 days after the start of protocol treatment.  
Participants will be followed for relapse and survival at 3 months after treatment, and then every 
six months until 3 years from start of treatment. Patients removed from the study treatment will 
continue to be followed for relapse and survival for up to three years following initiation of study 
treatment 
 
 
 
 


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TABLE OF CONTENTS 
SYNOPSIS AND SCHEMA 
1.
OBJECTIVES ......................................................................................................................7 
1.1 
Study Design ............................................................................................................7 
1.2 
Primary Objectives...................................................................................................7 
1.3 
Secondary Objectives...............................................................................................7 
2.
BACKGROUND .................................................................................................................7 
2.1 
Acute Myeloid Leukemia ........................................................................................7 
2.2 
Mitoxantrone, Etoposide, and Cytarabine ...............................................................8 
2.3 
Lenalidomide ...........................................................................................................9 
2.4 
Rationale ................................................................................................................12 
2.5 
Correlative Studies Background ............................................................................15 
3.
PARTICIPANT SELECTION ...........................................................................................15 
3.1 
Eligibility Criteria ..................................................................................................15 
3.2 
Exclusion Criteria ................................................................................................17 
3.3 
Inclusion of Women and Minorities ......................................................................17 
3.4 
Consent ..................................................................................................................17 
4.
REGISTRATION PROCEDURES ...................................................................................18 
4.1 
General Guidelines for DF/HCC Institutions ........................................................18 
4.2 
Registration Process for DF/HCC Institutions .......................................................18 
4.3 
General Guidelines for Other Investigative Sites ..................................................18 
4.4 
Registration Process for Other Investigative Sites.................................................18 
5.
TREATMENT PLAN ........................................................................................................19 
5.1 
Treatment Regimen ................................................................................................19 
5.2 
Pre-Treatment Criteria ...........................................................................................20 
5.3 
Agent Administration.............................................................................................20 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................22 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................23 
5.6 
Duration of Follow Up ...........................................................................................23 
5.7 
Criteria for Taking a Participant Off Study ...........................................................24 
6.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................24 
6.1 
Toxicity Management ............................................................................................25 
6.2 
Dose Modifications for Lenalidomide ...................................................................25 
6.3 
Dose Modifications for Mitoxantrone, Etoposide, Cytarabine ..............................27 
7.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................28 
7.1 
Expected Toxicities ................................................................................................29 
7.2 
Adverse Event Characteristics ...............................................................................30 
7.3 
Reporting Requirements for Specific Adverse Events ..........................................32 
7.4 
Expedited Adverse Event Reporting ......................................................................34 
7.5 
Routine Adverse Event Reporting .........................................................................37 


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8. 
PHARMACEUTICAL INFORMATION ..........................................................................38 
8.1 
Lenalidomide .........................................................................................................38 
8.2 
Mitoxantrone ..........................................................................................................41 
8.3 
Etoposide................................................................................................................43 
8.4 
Cytarabine ..............................................................................................................44 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................46 
9.1 
Laboratory Correlative Studies ..............................................................................46 
10. 
STUDY CALENDAR .......................................................................................................51 
10.1 
Pre-Treatment Evaluations.....................................................................................51 
10.2 
Bone Marrow Assessments ....................................................................................51 
10.3 
Post Treatment Evaluations ...................................................................................51 
10.4 
Long Term Follow Up ...........................................................................................52 
11. 
MEASUREMENT OF EFFECT........................................................................................53 
11.1 
Count Recovery .....................................................................................................53 
11.2 
Treatment-related Mortality ...................................................................................53 
11.3 
Relapse-Free and Overall Survival ........................................................................54 
11.4 
Second Malignancies .............................................................................................54 
11.5 
Evaluation of Response..........................................................................................54 
11.6 
Transfusion Requirements .....................................................................................55 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................55 
12.1 
Data Reporting .......................................................................................................55 
12.2 
Data Safety Monitoring..........................................................................................55 
12.3 
Multicenter Guidelines...........................................................................................56 
12.4 
Collaborative Agreements Language .....................................................................56 
13. 
STATISTICAL CONSIDERATIONS...............................................................................56 
14. 
PUBLICATION PLAN .....................................................................................................57 
REFERENCES ..............................................................................................................................59 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................63 
APPENDIX B     DATA AND SAFETY MONITORING PLAN ................................................66 
 
 
 


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1. 
OBJECTIVES 
 
1.1 
Study Design 
 
This is a Phase II study designed to test the efficacy of lenalidomide in combination with 
reinduction chemotherapy (mitoxantrone/etoposide/cytarabine) for patients with relapsed or 
refractory acute myeloid leukemia (AML).  
 
1.2 
Primary Objectives 
 
The primary objective of this study is to assess rates of complete remission (CR) and rates of 
complete remission with incomplete platelet recovery (CRp) after treatment with mitoxantrone, 
etoposide, cytarabine (MEC) and lenalidomide. 
 
1.3 
Secondary Objectives 
 
1. To evaluate the days to neutrophil recovery (the first of 3 days of ANC >500) 
2. To evaluate the days to platelet recovery (platelet count >20K unsupported) 
3. To evaluate the treatment-related mortality(the number of non-relapse related deaths in the 
first 50 days of starting treatment) 
4. To evaluate the transfusion support (the number of red blood cell and platelet transfusions 
needed in the first 50 days of treatment) 
5. To determine if certain genetic profiles of the leukemia predict for better response (optional 
correlate)  
 
2. 
BACKGROUND 
 
2.1 
Acute Myeloid Leukemia 
 
There are 12,000 new cases of acute myelogenous leukemia (AML) each year in the United 
States, with a median age of onset of 67. AML is characterized by an arrest in differentiation and 
uncontrolled proliferation of myeloid precursors in the bone marrow, leading to a decrease in the 
mature, infection fighting cells and severe infections. Unfortunately, successful treatment of 
AML remains a difficult challenge.   Although complete remission can be achieved in 
approximately 60- 70% of patients using combination chemotherapy with an anthracycline and 
cytarabine, the majority of patients relapse. (1) Therefore, approximately 70% of patients with 
AML may be candidates for reinduction therapy. If a second remission can be achieved, the 
patient may be a candidate for a potentially curative allogeneic stem cell transplant.  (2) 
 
Reinduction attempts are less successful than primary induction therapy, and therefore, the 5 
year disease free survival rate for all patients with AML is 25% and less than 10% for patients 
over the age of 60. (3, 4, 5) Since the majority of AML patients fail standard therapy, the 
development of more effective salvage reinduction chemotherapy is essential.  The prognosis is 
particularly poor for patients who are older, who have disease derived from myelodysplastic 
syndromes (MDS) or myeloproliferative disorders (MPD), and those with secondary AML from 
prior chemotherapy.  A complete remission is achieved in less than 40% of cases, with very poor 
survival rates of less than 10%. (6, 7). 


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The majority of relapses occur within the first year following primary induction. The high 
relapse rate has been attributed to the persistence of leukemic stem cells, which display 
resistance to cytotoxic chemotherapy.   While several large randomized studies such as the 
United Kingdom Medical Research Council have compared primary induction regimens, there is 
much less published on reinduction treatment. (8) 
 
2.2 
Mitoxantrone, Etoposide, and Cytarabine 
 
There are many regimens that have been employed for reinduction and no regimen is clearly the 
standard of care. One commonly employed regimen used to treat patients with relapsed and 
refractory AML involves mitoxantrone, etoposide, and cytarabine (MEC). (9) This regimen was 
introduced in 1991 for the treatment of relapsed or refractory AML and has been used alone and 
in combination with multi-drug resistance modulators and monoclonal antibodies. (10-12) 
 
One hundred and ninety-one AML patients participated in a multicenter study of MEC 
chemotherapy given as mitoxantrone 8 mg/m2, etoposide 80 mg/m2, and cytarabine 1 gm/m2 
daily for 6 days.  (10) Patients were randomized to MEC alone or to receive MEC plus the CD33 
antibody lintuzumab. Patients were either resistant to initial treatment or relapsed within 12 
months of initial therapy. Forty-six percent of patients were over age 60. Induction related deaths 
were 13%.  Side effects included nausea, vomiting, diarrhea, mucositis, elevated liver function 
tests, with mucositis reported in 21% of patients.  Patients received one course of induction 
chemotherapy.  Twenty-two percent of patients receiving MEC achieved a complete remission 
and 5% of patients achieved a CRp (complete remission without platelet recovery). Patients in 
CR received a second course of MEC with mitoxantrone 8 mg/m2 daily x 2 days, etoposide 80 
mg/m2 daily x 4 days, and cytarabine 1 gm/ m2 daily x 4 days. Median survival was 5 months.  
There was no difference in remission rates or survival between the MEC and MEC plus 
lintuzumab arms. 
 
Tallman and colleagues reported on 38 patients, median age 47 years, with MEC chemotherapy 
with or without the multidrug resistance inhibitor cyclosporine. (11) The drugs were dosed as 
follows: mitoxantrone 10 mg/m2 daily x 5 days, etoposide 100mg/ m2 daily x 5 days, and 
cytarabine 1g/m2 daily x 5 days. Patients were either in first recurrence after < 6 months of 
complete remission (11 patients), refractory to initial induction therapy or to one attempt at 
reinduction after recurrence (18 patients), in second recurrence (4 patients), or in recurrence after 
either allogeneic or autologous bone marrow transplantation (5 patients). There was one 
treatment related death.  The remission rate was 23% and the median survival 104 days. Patients 
received a second cycle of MEC in identical doses if there was persistent disease on Day +14. 
There was no difference in remission rate or survival between the patients that did or did not 
receive cyclosporine. 
A slightly modified version of the MEC regimen, randomized with and without the multidrug-
resistance inhibitor PSC-833 (Valspodar), was studied in 129 patients, median age 58 years, with 
relapsed or refractory AML and high-risk MDS. (12)  Eligible patients had relapsed less than 6 
months after first complete remission, after allogeneic or autologous stem cell transplantation, or 
were in second or greater relapse, refractory to induction chemotherapy, or secondary AML, or 
MDS with greater than 10% blasts. The MEC patients received mitoxantrone 8 mg/m2/d, 


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etoposide 100 mg/m2/d, cytarabine 1 gm/m2/d, all days 1 to 5.   The treatment related death rate 
(non relapse) was 10%.  Complete remission was achieved in 25% of the patients receiving 
MEC.  The median time to CR was 40 days; 25% of patients required 2 courses of treatment to 
achieve CR. Patients with secondary AML and MDS (no prior induction chemotherapy) did 
slightly better with 44% CR rate, compared to 19% CR rate for the relapsed patients. The median 
survival was 5 months. There was no difference in the CR rates, median disease-free survival, or 
overall survival between patients who received MEC alone or MEC plus PSC-833.  
More modern studies have shown similar remission rates. A retrospective analysis reported on 77 
patients with relapsed or refractory AML treated with MEC at the following doses: mitoxantrone 
8 mg/m2/d, etoposide 100 mg/m2/d, cytarabine 1 gm/m2/d, all days 1 to 5. (13) Eighteen percent 
of patients achieved a complete remission and the overall survival was 6.8%. There was trend to 
improved response in patients with favorable risk cytogenetics. 
There have been no prospective randomized trials comparing MEC chemotherapy to other 
salvage regimens. A retrospective study compared MEC to a clofarabine, cytarabine, and G-CSF 
regimen. The complete remission rate was 26% for reinduction after MEC, with no significant 
differences between the two regimens. (14)  Single dose mitoxantrone has been compared to the 
conventional divided dose mitoxantrone; the single dose regimen was inferior, mainly due to an 
increased incidence of toxic deaths. (15) 
Thus, patients receiving reinduction chemotherapy with MEC have a poor prognosis, with only 
18-26% entering complete remission, and further investigation is warranted.  There are several 
published versions with minor variations in the 5 day MEC regimen with no prospective 
comparisons. The current MEC version in use for relapsed AML at the Dana Farber/Harvard 
Cancer Center is mitoxantrone,8-10 mg/m2/day, by IV infusion over 6-10 minutes for 5 days, 
etoposide, 100 mg/m2/day, IV over 1 hour daily for 5 days, and cytarabine, 1000 mg/m2/day, IV 
over 1 hour daily for 5 days.  This regimen will serve as the basis chemotherapy regimen for this 
study. 
2.3 
Lenalidomide 
 
Lenalidomide is a proprietary IMiD® compound of Celgene Corporation.  IMiD® compounds 
have both immunomodulatory and anti-angiogenic properties which could confer antitumor and 
anti-angiogenic effects.   
Lenalidomide demonstrates pleiotropic activities in distinct cell types that result in direct 
antitumor effects on cancer cells, inhibition of stromal growth factor support, and enhancement 
of host anticancer immunity. (16-20)  The clinical activity of lenalidomide has been most notable 
in B-cell malignancies including MM, MCL, DLBCL, FL, and B-cell CLL. (21-24)  
The activity of lenalidomide may be further subdivided into the following categories: direct 
antiproliferative activity against hematopoietic tumor cells; immunomodulatory activity 
including upregulation of T cell and NK cell responses; and inhibition of monocyte responses, 
antiangiogenic activity, and pro-erythropoietic activity. 
Lenalidomide’s pleiotropic activities in a range of cell types including MM cells and immune 
effector cells suggest modulation of multiple molecular pathways. Studies conducted to identify 


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the molecular target(s) of lenalidomide have shown that it physically associates with the protein 
cereblon (encoded by the CRBN gene), a protein required for the teratogenic effects of 
thalidomide in zebrafish and chicken embryos (25).  Cereblon is a substrate receptor for an 
ubiquitin E3-ligase complex containing deoxyribonucleic acid (DNA) damage-binding protein 1 
(DDB1), cullin 4 (CUL4), and regulator of cullins 1 (Roc1) proteins (CRL4cereblon) (25).  Upon 
binding to Cereblon, lenalidomide induces the ubiquitination of substrate proteins, including 
Ikaros (encoded by the gene IKZF1) and Aiolos (encoded by the gene IKZF3), thus targeting 
them for proteasomal-dependent degradation (26-28).  It was also demonstrated that the 
expression of Cereblon in MM cells is linked to the anti-proliferative effects of lenalidomide and 
to the acquired resistance in vitro (29-30).  The downstream anti-proliferative and pro-apoptotic 
effects of Ikaros and Aiolos are linked to the subsequent downregulation of the MM growth-
promoting factors c-Myc and IRF4.  
Ikaros and Aiolos are zinc finger transcription factors initially discovered as regulators of the T 
cell receptor and are required for proper hematopoiesis particularly lymphocyte development and 
plasma cell maturation. Cereblon expression also mediates the T-cell response to lenalidomide 
through the targeted degradation of Ikaros and Aiolos (26,29).  In activated T cells in which 
cereblon was transiently decreased, interleukin-2 (IL-2) and TNF-α induction by lenalidomide 
was markedly reduced.  Since IL-2 and TNF-α are important for tumor surveillance by activated 
T cells, these results indicate that some of the immunomodulatory effects of lenalidomide are 
mediated via initial binding to cereblon.  Specifically, upon engagement with the CRL4cereblon, 
lenalidomide induced ubiquitination and proteasomal degradation of Ikaros and Aiolos in T cells 
in a time- and concentration-dependent manner (26-28).  Because Ikaros and Aiolos are known 
repressors of the IL-2 promoter, their degradation in response to lenalidomide and other IMiDs® 
compounds, explains the enhanced T cell IL-2 production . 
In summary, lenalidomide exhibits potent anti-tumor activity in B cell malignancies, which 
appears to be mediated through the protein target, cereblon.  While specific cereblon interaction 
networks are still to be defined, these results are key for further understanding of the mechanism 
of lenalidomide effects.  
 
2.3.1 Clinical experience in multiple myeloma with lenalidomide 
 
In 2 phase I studies in multiple myeloma, a total of 41 patients have been treated with 
lenalidomide.  In one study at the University of Arkansas, 15 patients who relapsed or were 
refractory to high dose melphalan therapy with stem cell transplant were treated for 4 weeks in 
an open-label safety study and were permitted to continue therapy in an extension phase of the 
trial.  Patient cohorts were treated at the following daily doses: 5mg, 10mg, 25mg, and 50mg.  
(31)    In a similar study at the Dana Farber Cancer Institute, 27 patients with rapidly advancing 
refractory multiple myeloma were enrolled.  (32) 
Anti-myeloma activity was observed in each of these 2 phase I studies.  Decreases in neutrophil 
and platelet counts were the dose-limiting toxicities associated with lenalidomide.  The 
maximum tolerated dose (MTD) was not reached within 28 days. Due to dose modifications 
associated with myelosuppression observed beyond Day 28 at the 25mg and 50mg daily dose 
levels, the dose schedule most widely used in future studies has been lenalidomide 25 mg on 
Days 1-21, repeated every 28 days.   


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Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum 
blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg).  
Plasma lenalidomide declined in a monophasic manner with elimination half-life ranging from 
2.8 to 6.1 hours on both Day 1 and 28 at all 4 doses.  No plasma accumulation was observed with 
multiple daily dosing.  Peak and overall plasma concentrations were dose proportional over the 
dosing range of 5mg to 50mg. (33)  
A multicenter, randomized, phase II trial compared 2 syncopated dose schedules of lenalidomide 
used alone or in combination with dexamethasone in the treatment of relapsed or refractory 
multiple myeloma.  All patients were treated on Days 1-21 of a 28-day cycle.  Patients treated 
with 15mg BID experienced more myelosuppression and dose reductions compared with patients 
treated with 30mg daily.  Anti-myeloma activity was observed with each dose and schedule of 
single agent lenalidomide.  The addition of dexamethasone to lenalidomide yielded responses in 
some patients who had not responded to lenalidomide alone.  (34). 
A phase II trial utilizing lenalidomide plus dexamethasone for newly diagnosed multiple 
myeloma patients was reported by the Mayo Clinic. Lenalidomide was given orally 25 mg daily 
on days 1-21 of a 28-day cycle. Dexamethasone was given orally 40 mg daily on days 1-4, 9-12, 
17-20 of each cycle. Objective response was defined as a decrease in serum monoclonal protein 
by 50% or greater and a decrease in urine M protein by at least 90% or to a level less than 200 
mg/24 hours, confirmed by two consecutive determinations at least 4 weeks apart. Thirty-one of 
34 patients achieved an objective response, including 2 (6%) achieving complete response (CR), 
and 11 (32%) meeting criteria for both very good partial response and near complete response, 
resulting in an overall objective response rate of 91%. Of the 3 remaining patients not achieving 
an objective response, two had minor response (MR) and one stable disease. Forty-seven percent 
of patients experienced grade 3 or higher non-hematologic toxicity, most commonly fatigue 
(15%), muscle weakness (6%), anxiety (6%), pneumonitis (6%) and rash (6%). Rev/Dex is a 
highly active regimen with manageable side effects in the treatment of newly diagnosed 
myeloma.  (35) 
Celgene Corporation sponsored 2 multicenter, randomized, double-blinded, placebo-controlled 
phase III trials [1 U.S. (MM-009) and 1 international (MM-010)] in patients with relapsed or 
refractory multiple myeloma. (36)   More than 350 patients were enrolled into each of these 
studies.  All patients had to be considered sensitive to dexamethasone and were treated with 
dexamethasone 40mg qd, Days 1-4, 9-12 and 17-20.  In addition to receiving dexamethasone, 
patients were randomized to lenalidomide 25mg qd or placebo, Days 1-21.  Cycles were repeated 
every 28 days.   After 4 cycles, there was a predetermined reduction of the dexamethasone dose 
to 40mg qd, Days 1-4 repeated every 28 days.  In both studies, a pre-specified interim analysis 
conducted by an Independent Data Monitoring Committee demonstrated that subjects receiving 
the combination of lenalidomide (Len) plus dexamethasone (Dex) had significantly longer times 
to progression and higher response rates than those treated with single-agent dexamethasone.  
These studies led to the FDA approval of lenalidomide in combination with dexamethasone for 
the treatment of multiple myeloma in patients that have received at least one prior therapy. 
 
2.3.2 Clinical experience in myelodysplastic syndromes (MDS) with lenalidomide 
 


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An exploratory trial in 43 MDS patients with transfusion dependent or symptomatic anemia was 
conducted at the University of Arizona.  (37)    Patients received lenalidomide at doses of 25mg 
or 10mg per day, or of 10mg on Days 1-21, repeated every 28 days.  All patients had had no 
response to erythropoietin or had a high endogenous erythropoietin level.  Response rates were 
similar across the 3 dose schedules used.  Responses were observed in 24 patients overall (56%) 
including 21 patients with a major response and 20 patients with sustained transfusion 
independence.  Patients with a major response reached a median hemoglobin level of 13.2 grams 
per deciliter, with a corresponding 5.3 grams per deciliter median increase from baseline.  After a 
median follow-up of 81 weeks, the median duration of major response had not been reached and 
was more than 48 weeks.  Of 20 patients with karyotypic abnormalities, 10 (50%) patients had a 
complete cytogenetic remission.  The response rate was highest in patients with a clonal 
interstitial deletion involving chromosome 5q31.1 (10 out of 12, 83%).  Neutropenia and 
thrombocytopenia were the most common adverse events, and resulted in dose delays or 
reductions in 25 patients (58%). 
Celgene Corporation sponsored a multicenter trial (MDS-003) of 148 MDS patients with a clonal 
interstitial deletion involving chromosome 5q31.1.  Lenalidomide was given at a dose of 10mg 
on Days 1-21, repeated every 28 days, to 44 patients, and at a dose of 10mg daily to the other 
104 patients.  Transfusion independence was achieved in 93 patients (64%), with a median 
hemoglobin increase of 3.9g/dl. Cytogenetic response was achieved in 76% of transfusion 
independent patients with 55% achieving a cytogenetic complete response. Pathologic complete 
response was documented in 32 out of 110 (29%) evaluable patients.  With a median follow-up 
of 9.3 months, the median response duration had not been reached.  Neutropenia (39%) and 
thrombocytopenia (35%) were the most common adverse events requiring dose delays or 
reductions.   (38) 
Another Celgene sponsored trial (MDS-002) in patients with low to intermediate-1 risk MDS 
enrolled 215 patients, of whom, 166 were documented to have low to intermediate-1 risk MDS.  
Among the patients with documented low to intermediate-1 risk MDS, 84 patients (51%) 
responded to treatment.  Transfusion independence was achieved in 54 patients (33%) and 30 
patients (18%) achieved a minor response, defined as a 50% or greater decrease in blood 
transfusion requirement.  The median duration of transfusion-independence was 41 weeks.  The 
median baseline hemoglobin level was 8.0g/dl, which increased by 3.2g/dl in responding 
patients.  Among 20 patients evaluable for cytogenetic response, 9 patients (45%) experienced a 
cytogenetic remission.  (39) 
Sixty-seven percent of patients with del (5q) MDS achieved transfusion independence after 
treatment with lenalidomide. (39) Treatment related cytopenia correlated with clinical response 
in patients with del (5q) myelodysplasia. (40)  Treatment with lenalidomide also resulted in 
responses in patients with normal cytogenetics. (41) Two hundred and fourteen patients received 
lenalidomide 10 mg daily or 10mg days 1-21 of a 28 day cycle. Patients had low or intermediate-
1 risk MDS non 5q- and were transfusion dependent. Transfusion independence was achieved in 
26% of patients.  
2.4 
Rationale 
 
Revlimid® (lenalidomide) is indicated for the treatment of patients with transfusion-dependent 
anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 


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5q cytogenetic abnormality with or without additional cytogenetic abnormalities.  Revlimid® is 
also approved in combination with dexamethasone for the treatment of patients with multiple 
myeloma and Revlimid® has recently been approved in the treatment of patients with mantle cell 
lymphoma whose disease has relapsed or progressed after two prior therapies, one of which 
included bortezomib.  
 
2.4.1 Role of Lenalidomide in Acute Myeloid Leukemia 
Recently, lenalidomide has been shown to have activity in acute myelogenous leukemia, given at 
a dose of 35-50 mg daily as a single agent. (42-44)  Chandler and colleagues performed a dose 
escalation trial of lenalidomide. The 50 mg dose was the maximum tolerated dose with higher 
doses resulting in dose-limiting fatigue. (42)  Blum et al reported on a Phase I study of 31 
patients with relapsed or refractory AML who received lenalidomide in doses of 25-75 mg daily 
Days 1-21 of a 28 day cycle. (43)  Fatigue was considerable at a dose of 75 mg. Five patients 
achieved a complete response. 
Thirty-three patients over age 60 received lenalidomide 50 mg daily in 2 28 day cycles, followed 
by a low dose lenalidomide (10 mg) maintenance if they did not progress. Overall complete 
remission/complete remission with incomplete platelet recovery rate was 30%, with patients with 
low blast counts more likely to respond. (44) The CR rate was 53% in patients completing the 
high dose lenalidomide treatment.  The median time to CR was 30 days and the duration of CR 
was 10 months. The most common toxicities were neutropenia, thrombocytopenia, and infection. 
Two patients with AML with trisomy 13 cytogenetic abnormality responded to lenalidomide. 
(45) One patient received lenalidomide 50 mg daily for 14 days, followed by 30 days off therapy 
and 21 days of lenalidomide 50 mg daily, and the other patient received a dose of 35 mg daily 
Days 1-21 of repeated 28 day cycles. Both patients achieved a complete remission, and relapsed 
after 9 months of CR.  
Sekeres and colleagues treated 37 older AML patients with del (5q) with lenalidomide 50 mg 
daily for induction, and 10 mg daily for maintenance. (46) The median age was 74 years. 
Fourteen patients completed induction, and five patients achieved a complete remission.  
Combinations of lenalidomide with standard chemotherapy are currently under investigation. 
Laboratory correlates of the AML patients treated with lenalidomide indicated suppression of the 
tumor clone, as assessed by fluorescence in situ hybridization for del (5q31). (47)  Twenty-eight 
patients with AML or high risk MDS, all with chromosome 5 abnormalities, alone or in 
combination, were treated with lenalidomide 30 mg daily for 16 weeks. Nineteen percent of 
patients had a major cytogenetic response and eight percent had a minor cytogenetic response. 
Thirty-five percent of patients had a clinical response, including 9 of 10 who completed the full 
16 weeks of treatment.  
Data from Ohio State University and others has shown that microRNA (miR)-181 a and b is 
associated with improved outcomes in cytogenetically normal and cytogenetically abnormal 
AML. (48,49)   More recent work suggests that lenalidomide increases miR-181a and b, which 


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may contribute to improved outcomes, and is consistent with pretreating patients with 
lenalidomide prior to induction chemotherapy. (50) 
Lenalidomide has also been used to treat relapse after allogeneic stem cell transplant for AML; 
lenalidomide was given at a dose of 10 mg daily and CR was achieved. (51) 
Recent data suggests lenalidomide may affect clonal architecture in patients with 
myelodysplasia. (52) Loss of treatment efficacy coincided with re-expansion of the dominant 
subclone. 
A Phase I study (07-006) of lenalidomide and bortezomib for patients with MDS and AML has 
been completed at Massachusetts General Hospital and Dana Farber Cancer Institute. (53) 
Lenalidomide was given at a dose of 10 mg daily, Days 1-21 of 28 days cycles. The drug was 
tolerated well. 23 patients (14 men) were enrolled; one patient was inevaluable due to disease 
progression prior to starting protocol therapy. The median age was 73 years (range 54-87). There 
was 1 DLT observed, neutropenia, in 6 patients treated with 1.0 mg/m2 bortezomib and no DLTs 
at 0.7 or 1.3 mg/m2. The median number of cycles was 2 (range 2-9). Grade ≥ 3 toxicities 
possibly attributable to the treatment at any dose level were: anemia (2), thrombocytopenia (10), 
leukopenia (3), infection (1), rash (2), dyspnea (1), dizziness (1), hypotension (1), pneumonia (2) 
and neuropathy (1). Among the 14 patients with MDS, 1 patient with RARS experienced a CR 
and 2 with RAEB-2 experienced marrow CR (mCR). Among the 8 patients with AML, there was 
1 CR.  
 
Protocol 12-202, Phase I study of Lenalidomide plus mitoxantrone, etoposide, and cytarabine for 
patients with relapsed and refractory AML has just been completed at DF/HCC. Results were 
presented in abstract form at the American Society of Hematology, December 2015. (54)  
 
The primary objective of this Phase I trial was to evaluate the safety of lenalidomide in 
combination with MEC for relapsed acute myelogenous leukemia and determine a safe Phase II 
dose and schedule. The secondary objectives included time to neutrophil (>500) and platelet 
recovery (> 20K), the complete response rate with and without platelet recovery, and the 
treatment-related mortality within the first 45 days. Patients received lenalidomide in escalating 
doses at dose levels:  5 mg, 10 mg, 25 mg and 50 mg. Lenalidomide was given initially Days 1-
14, and then due to neutropenia was decreased to Days 1-10. The chemotherapy was given as 
follows: Mitoxantrone 8 mg/m2/day Days 4-8, Etoposide 100 mg/m2/day Days 4-8, and 
Cytarabine 1000 mg/m2/day Days 4-8. Thirty-six patients were enrolled with a median age of 61 
years. Forty-five percent of patients had received 2 or more prior chemotherapy regimens, and 
22% had received a prior stem cell transplant.  Thirteen patients entered complete remission and 
one patient had complete remission with incomplete count recovery for a response rate of 39%. 
The median time to ANC > 500 was 30 days and the median time to platelet recovery > 20,000 
was 34 days. Two of 6 patients treated with lenalidomide for 14 days had no count recovery at 
Day 42. After the dose adjust to 10 days, only 1 of 13 patients at lenalidomide 50 mg daily x 10 
days had prolonged count recovery. Thus, the recommended phase 2 dose is 50 mg daily for 10 
days. There were 4 deaths on study, deemed unrelated to study drug. One patient died of sepsis, 
one of infection, and two of respiratory failure. 


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We propose to study the efficacy of lenalidomide and MEC chemotherapy as reinduction 
treatment in patients with relapsed and refractory AML.  The survival is poor for patients with 
relapsed or refractory leukemia treated with standard chemotherapy. Lenalidomide has been 
demonstrated to have significant activity in AML. Our Phase I study demonstrated that 
lenalidomide in combination with MEC chemotherapy will be safely tolerated.  Patients with 
relapsed and refractory AML will be eligible for this study. If this combination proves to be 
effective, a multicenter Phase III study would be considered. 
 
2.5 
Correlative Studies Background 
 
Acute myeloid leukemia (AML) is a disease characterized by the combinatorial action of 
multiple somatic mutations that lead to an arrest in normal hematopoietic differentiation and 
uncontrolled growth of immature bone marrow myeloid blasts.  (55, 56) 
 
Advances in gene sequencing technology over the past decade have allowed for the identification 
of over 50 recurrent mutations in AML patients. Mutational testing of a limited number of genes 
is already considered an integral part of standard clinical practice. The presence of mutations in 
FLT3 and NPM1 help define prognosis and determine treatment algorithms. Recent clinical trial 
data have demonstrated the clinical efficacy of the tyrosine kinase inhibitor midostaurin in the 
presence of a FLT3 mutation. AML patients with IDH mutations are now being enrolled in 
clinical trials utilizing small molecule inhibitors of this mutant enzyme (57). Some mutations 
may also predict response or resistance to certain therapeutic interventions. In myelodysplasia, a 
related myeloid disease, the finding of isolated deletion of 5q is already an approved indication 
for the use of lenalidomide (58). However, concomitant mutations in TP53 have been 
demonstrated to predict a poor response to treatment with lenalidomide in these patients (59). 
Whether this observation holds true in AML remains an open question. Identifying genetic 
markers that predict response to specific agents so that we can triage patients appropriately is an 
important and unmet clinical need.  
 
We now routinely perform DNA sequencing of recurrently mutated genes from clinical samples 
using next generation sequencing assays, including the Rapid Heme Panel or the Heme 
SNaPshot assay. These assays provide targeted next-generation sequencing of recurrently 
mutated genes as well as high-resolution genomic copy number data at these loci. Mutation and 
copy number status will be determined. With this genetic information we can classify patients 
into molecularly defined groups; for instance, de novo AML, secondary AML and TP53 
associated AML (60). We can also look for correlations between specific genetic lesions and 
response to therapy in this clinical trial. In doing this, we hope to identify specific factors 
associated with response and primary resistance to lenalidomide in AML.  
 
3. 
PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study.  All required tests must be performed within 21 days of the start of 
treatment. 
 


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3.1.1 Acute myelogenous leukemia diagnosed by WHO criteria with one of the following 
(patients with biphenotypic leukemia are eligible, provided that the treating physician 
determines an AML treatment regimen is appropriate) 
• 
Primary refractory disease following > 1 cycle of induction chemotherapy 
• 
First relapse or higher.  Patients with primary or secondary acute myelogenous 
leukemia are eligible.   
3.1.2 Age 18-70 years old 
3.1.3 LVEF > 50 % 
3.1.4 ECOG Performance status 0-2 
3.1.5 Able to adhere to study schedule and other protocol requirements. 
3.1.6 Participants must have normal organ function as defined below, unless felt due to 
underlying disease and approved by the overall PI. Patients with Gilbert’s disease may 
have total bilirubin up to < 3 x institutional ULN. 
• 
Creatinine  < 2.0mg/dl, and eGFR ≥ 60 mL/min 
• 
Total bilirubin  < 1.5 x institutional ULN 
• 
AST (SGOT) and ALT (SGPT) < 3 x institutional ULN 
3.1.7 Patients may receive hydroxyurea, steroids, or leukapheresis as necessary until Day 5 of 
treatment. 
3.1.8 Patients must give voluntary written informed consent and HIPAA authorization before 
performance of any study-related procedure not part of normal medical care, with the 
understanding that consent may be withdrawn by the subject at any time without 
prejudice to future medical care. 
3.1.9 Patients may have had prior treatment for MDS or AML, including prior lenalidomide for 
MDS or AML or another condition. 
3.1.10 Patient may have had prior autologous or allogeneic transplant (family member, unrelated 
donor, or cord blood) if there is at least 90 days between transplant and study entry.  
3.1.11 Patients may also have had donor lymphocyte infusion if there is at least 60 days between 
donor lymphocyte infusion and study entry.  
3.1.12 Patients on immunosuppression are also eligible. 
3.1.13 Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL prior to receiving treatment with 
lenalidomide, and must either commit to continued abstinence from heterosexual 
intercourse or begin TWO acceptable methods of birth control, one highly effective 
method and one additional effective method AT THE SAME TIME, at least 28 days 
before she starts taking lenalidomide.  FCBP must also agree to ongoing pregnancy 
testing.  Men must agree to use a latex condom during sexual contact with a FCBP even 
if they have had a successful vasectomy.   
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
3.1.15 All study participants must be registered into the mandatory Revlimid REMS ® program, 
and be willing and able to comply with the requirements of the REMs ® program.  
Females of reproductive potential must adhere to the scheduled pregnancy testing as 
required in the Revlimid REMS® program. 
                                                 
 
† A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses 
at any time in the preceding 24 consecutive months) 


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3.2 
Exclusion Criteria 
 
3.2.1 Known hypersensitivity to thalidomide or lenalidomide (if applicable). 
3.2.2 The development of erythema nodosum if characterized by a desquamating rash while 
taking thalidomide or similar drugs. 
3.2.3 Known seropositive for human immunodeficiency virus (HIV). HIV testing is not 
required. Hepatitis testing is not required. 
3.2.4 Patients who have had a myocardial infarction within 6 months of enrollment or has New 
York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, 
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia 
or active conduction system abnormalities. 
3.2.5 Any serious medical condition laboratory abnormality or psychiatric illness that would 
prevent the subject from signing the consent form. 
3.2.6 Any condition, including laboratory abnormalities, that in the opinion of the investigator 
places the subject at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study. 
3.2.7 Patients with major surgery within 28 days prior to treatment. 
3.2.8 Patients with any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this protocol. 
3.2.9 Patient has received an investigational agent or cytotoxic chemotherapy (excluding 
hydroxyurea) within 7 days of study entry. If an LP is performed for clinical care, 
intrathecal chemotherapy (although not systemic chemotherapy) may be given as 
prophylaxis per institutional standard of care, but should be completed >24 hours prior to 
administration of protocol therapy. 
3.2.10 Patients with acute promyelocytic leukemia. 
3.2.11 Females who are pregnant  
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  Women and 
minorities are included in the eligibility criteria. We do not anticipate that women or minorities 
will have increased toxicity with this treatment approach. Gender, race and ethnicity will be 
recorded in our database, per standard procedures. 
 
3.4 
Consent 
 
Patients who are referred to the participating institutions for consideration of treatment of acute 
myelogenous leukemia will be considered for participation.  Patients with AML who have 
relapsed or refractory disease are eligible for this study. Treatment recommendations are 
discussed thoroughly with patient and family.  The alternative forms of therapy, as far as they 
exist, are presented as objectively as possible. The risks and hazards of the procedure are 
explained to the patient and family.  It will be pointed out specifically that some aspects of this 
treatment are considered experimental.  Consent is obtained using forms approved by 
participating site’s Institutional Review Board. 
 


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4. 
REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at Massachusetts General Hospital by the 
Coordinating Center.  All sites should contact the Coordinating Center to verify treatment 
availability. 
 
Following registration, participants may begin protocol treatment. Issues that would cause 
treatment delays should be discussed with the Principal Investigator/Sponsor. If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled.  The Coordinating Center should be notified of cancellations as soon as 
possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a subject, the following documents should be completed by the participating 
institution and forwarded to the Coordinating Center: 
 
• Copy of source documentation for inclusion/exclusion criteria and screening procedures, 
including but not limited to 
 
Pathology report 
 
Medical history and physical exam 
 
Laboratory reports 
 
Radiology results/reports 
 
Echo or MUGA report 
 
Concomitant medication list 


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• Demographics information 
• Signed study consent form 
• Study Entry Note 
• HIPAA authorization form, if applicable 
• Eligibility checklist 
 
The Coordinating Center will review the above documentation to verify eligibility and consent. 
To complete the registration process, the Coordinating Center will follow DF/HCC Standard 
Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP #: 
REGIST-101) and register the participant on the protocol.  Once registered, a confirmation email 
with the participant study number, and if applicable the dose treatment level, will be sent to the 
participating site.   
NOTE:  Registrations can only be conducted by the Coordinating Center during the business 
hours of 8:30 AM and 5:00 PM Eastern Standard Time (or Eastern Daylight Time when 
applicable), Monday through Friday.  A complete registration packet, including all documents 
listed above, must be received at least 24 hours prior to the anticipated registration to ensure 
adequate review.  Same day treatment registrations will only be accepted with prior notice and 
discussion with the DF/HCC Lead Institution.  
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered.  
 
5. 
TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
Table 1: Schema for reinduction chemotherapy treatment 
 
 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Mitoxantrone 
(intravenous) 
 
 
 
X 
X 
X 
X 
X 
 
 
Etoposide 
(intravenous) 
 
 
 
X 
X 
X 
X 
X 
 
 
Cytarabine 
(intravenous) 
 
 
 
X 
X 
X 
X 
X 
 
 
Lenalidomide 
(oral) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patients will receive all treatment on an inpatient basis. All chemotherapy doses will be based on 
actual weight obtained on Day 1 of the treatment cycle.  The total administered doses of the 
MEC chemotherapy will be calculated using actual weight and may be rounded up or down 
within a range of 5% of the actual calculated dose. Any dose modifications in the 
mitoxantrone, etoposide, and cytarabine chemotherapy are per physician discretion or 
institutional practice (please refer to section 6.3, table 5), with approval from the overall PI.  


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Administer chemotherapeutic agents according to institutional policies and procedures. 
Mitoxantrone will be administered first, followed by etoposide, followed by cytarabine. 
Patients will receive only one cycle of treatment as outlined in tables 1 and 2. There is no 
retreatment as a part of this protocol. See section 6 (Dosing delays/Dose modifications) for 
further information on dose modifications and interruptions.  Premedications will be given 
per institutional standards. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Following reinduction therapy, patients may be treated further according to their treating 
physician. Patients who achieve a CR or CRi, as well as those who are otherwise deemed 
eligible, are recommended to proceed with allogeneic hematopoietic stem cell transplantation if 
possible. Otherwise patients are recommended to have further consolidation according to their 
treating physicians. 
 
5.2 
Pre-Treatment Criteria 
Patients must meet eligibility in order to be enrolled on the study.  Eligibility criteria does not 
need to be reconfirmed on Day 1 of treatment. There are no additional pretreatment criteria on 
Day 4 of treatment. 
 
5.3 
Agent Administration 
 
Treatment will be administered on an inpatient basis. Expected toxicities and potential risks for 
mitoxantrone, etoposide, cytarabine, and lenalidomide are outlined in Toxicities and Dosing 
Delays/Dose Modification (section 6). 
 
 
Administer chemotherapeutic agents according to institutional policies and procedures. 
Lenalidomide should be administered prior to MEC each day. During the administration of 
MEC, mitoxantrone will be administered first, followed by etoposide, followed by 
cytarabine. 
 
General dosing guidelines for lenalidomide are provided below.  Please refer to the dosage and 
Table 2: Dosing information  
 
Agent 
Dose 
Route 
Schedule 
Mitoxantrone 
8 
mg/m2/day 
IV infusion over approx 
6-10 minutes daily or per 
institutional standards for 
5 days  
Days 4 – 8  
Etoposide 
100 
mg/m2/day 
IV over approx 1 hour 
daily or per institutional 
standards for 5 days  
Days 4 – 8 
Cytarabine 
1000 
mg/m2/day 
IV over approx 1 hour daily 
or per institutional 
standards for 5 days  
Days 4 – 8 
Lenalidomide 
50 mg 
Orally 
Days 1– 10  


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administration schedule specified in the prescribing information. 
 
5.3.1 Lenalidomide Dosing Guidelines 
 
Lenalidomide should be taken orally at about the same time each day. The capsules should not 
be opened, broken, or chewed.  Lenalidomide capsules should be swallowed whole, preferably 
with water, either with or without food. If a dose of lenalidomide is missed, it should be taken as 
soon as possible on the same day (until midnight). If it is missed for the entire day, it should not 
be made up. Vomited doses will not be made up. Do not take 2 doses at the same time. 
 
5.3.1.1 
Patients Receiving Concomitant Digoxin 
 
Periodic monitoring of digoxin levels in patients receiving this medication concomitantly with 
lenalidomide is recommended in accordance with clinical judgment and based on standard 
clinical practice. 
 
5.3.1.2 
Patients Receiving Concomitant Warfarin 
 
Monitoring of warfarin concentration in accordance with standard practice is advised during 
treatment with lenalidomide. 
 
5.3.1.3 
Elderly Patients 
 
No dedicated clinical studies have been conducted to evaluate the PK of lenalidomide in the 
elderly. However, results of population PK analyses (subject ages ranging from 39 to 85 years 
old) suggest that age does not influence the disposition of lenalidomide. No lenalidomide dose 
adjustments are needed.  
 
5.3.1.4 
Patients with Impaired Renal Function 
 
Lenalidomide is primarily excreted unchanged by the kidney; for other approved indications, 
starting dose adjustment is recommended in patients with CKD. Based on a PK study in subjects 
with CKD due to nonmalignant conditions, lenalidomide starting dose adjustments are 
recommended for patients with CrCl < 60 mL/min; therefore, patients must have a CrCl ≥ 60 
mL/min to be eligible for this study. 
 
Because lenalidomide is primarily excreted unchanged by the kidney, monitoring of renal 
function is advised.  No dose adjustments are required for patients with CrCl  ≥ 60 mL/min. 
Patients must have eGFR of  ≥ 60 mL/min and Cr < 2 mg/dL to enroll on the study. Refer to 
Section 6.2, Table 4 for lenalidomide dose adjustment recommendations if patients develop 
worsened renal function while on treatment. 
  
5.3.1.5 
Prohibited Medications 
 
Any investigational agent or medication intended to treat the malignancy. 
 


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5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 Encouraged Supportive Care and Allowed Concomitant Medications 
 
Infection Prophylaxis may be per institutional guidelines. The following practices are suggested 
prophylactic antibiotics (such as Levaquin or other appropriate agent) against gram negative 
organisms while patient is neutropenic; antiviral therapy against herpes viruses with acyclovir or 
an appropriate substitution; and antifungal prophylaxis with fluconazole (or another appropriate 
agent). Patients should have excellent oral care per institutional standards. Patients with fever 
and neutropenia should be treated with broad spectrum antibiotics per institutional guidelines. 
 
Recombinant Granulocyte Colony Stimulating Factor (G-CSF) may be administered 
intravenously or subcutaneously at the discretion of the investigator and per institutional 
guidelines. G-CSF is recommended for patients older than age 60 after the completion of 
chemotherapy and for all patients with serious infections. 
 
Prophylaxis against tumor lysis syndrome is recommended and can be administered per 
institutional guidelines. 
 
Transfusion support per Dana-Farber/Harvard Cancer Center guidelines will be provided, and 
patients may be managed per local standards. 
 
Central venous access is suggested prior to the start of chemotherapy. 
 
Antiemetics will be used per standard practices. 
 
Hyperalimentation (TPN) will be provided at the treating physician’s discretion.  
 
Decadron eye drops are recommended and can be dosed per institutional guidelines.  Suggested 
dosing is as follows: 
 
• 
Two drops of dexamethasone suspension 0.1% to both eyes every 6 hours starting with first dose 
of cytarabine on day 4 and continued for 72 hours after the last dose of cytarabine on day 8. 
 
Neurologic assessments for cerebellar function are recommended while patient is receiving 
cytarabine. 
 
After hospitalization, subjects will be followed closely to monitor for complications related to 
chemotherapy.  Patients will receive standard post-chemotherapy discharge teaching and 
guidelines to prevent infection. 
 
Prophylactic anticoagulation is not recommended considering the low platelet count after 
induction chemotherapy. 
 
5.4.2 Anticoagulation consideration 
 


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Lenalidomide increases the risk of thrombotic events in patients who are at high risk or with a 
history of thrombosis, in particular when combined with other drugs known to cause thrombosis. 
Due to the thrombocytopenia with this chemotherapy regimen, anticoagulation and antiplatelet 
agents are not recommended. 
 
When lenalidomide is combined with other agents such as steroids (e.g. dexamethasone, 
prednisone), anthracyclines (Doxil, Adriamycin) and erythropoietin, the risk of thrombosis is 
increased.   
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) or those listed in table 3 as requiring treatment 
discontinuation 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
• 
The subject needs a medication that is not part of this study (e.g additional 
chemotherapy for relapsed or progressive disease) 
• 
The investigator feels this study protocol would not be in the subject’s best interest 
• 
Patient completed all treatment as outlined in the protocol 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  
Alternative care options will be discussed with the participant. 
 
The reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF).  The DF/HCC research team will update the relevant 
Off Treatment/Off Study information in OnCore.  The Coordinating Center will update this 
information for external site participants.  
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Andrew Brunner, MD at 
.  
 
5.6 
Duration of Follow Up 
 
Participants will be followed for at least 50 days after the start of protocol treatment.  
Participants will be followed for relapse and survival at 3 months after treatment, and then every 


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six months until 3 years from start of treatment, including those patients who are removed from 
the study treatment prior to completing the 50 day toxicity period. 
 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
Study subjects may withdraw their consent to participate in this trial at any time.  Once 
withdrawn, the study subject will receive usual care considered standard and routine for their 
individual case. 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Completed all follow-up per protocol 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).  The DF/HCC research team will update the relevant 
Off Treatment/Off Study information in OnCore.  The Coordinating Center will update this 
information for external site participants. 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Any dose modifications or delays in the reinduction chemotherapy regimen of mitoxantrone, 
etoposide, and cytarabine should be per the treating physician and institutional practice, with 
approval from the overall PI (also please refer to section 6.3, table 5).  
 
There may be two dose reductions in lenalidomide per patient. Reduction of lenalidomide 
dose may be modified as follows: 
 
Table 3: Lenalidomide Dose Reductions 
Dose Level 
Lenalidomide dose 
1 (starting dose) 
50 mg 
-1 
25mg 
-2 
10 mg 
 
No Lenalidomide will be given after Day 10, even if there are missed doses. 
 
Dose delays and modifications will be made as indicated in Table 4. The descriptions and 
grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A copy of the 
CTCAE version 4.03 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 


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6.1 
Toxicity Management 
 
Significant toxicity is expected in this leukemia reinduction protocol.  Patients will receive 
supportive care and medical management of toxicity. 
 
Antiemetics are recommended for management of nausea and vomiting.  
 
Stool cultures for C. Diff are recommended for patients with diarrhea.  If negative, 
antidiarrheals should be used as clinically indicated 
 
For management of neutropenia/fever myeloid growth factors can be considered. Platelet 
transfusions should be considered for management of patients with a platelet count of <10K or 
bleeding.  
 
Local steroid creams are recommended as clinically indicated for the management of rashes.   
 
6.2 
Dose Modifications for Lenalidomide 
 
 
Table 4: Dose modifications for Lenalidomide 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Vomiting 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Diarrhea 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Neutropenia 
 
no change in 
dose 
no change in 
dose 
no change in dose 
Continue 
lenalidomide dose. 
Follow CBC. 
Consider G-CSF. 
Thrombocytopenia 
 
no change in 
dose 
no change in 
dose 
Continue 
lenalidomide 
dose. Follow 
CBC. Consider 
platelet 
transfusion 
Continue 
lenalidomide dose. 
Follow CBC. 
Consider platelet 
transfusion 
Neutropenia 
associated with 
fever (temperature ≥ 
38.5º C) 
N/A 
N/A 
Continue 
lenalidomide 
dose. Follow 
CBC. Consider G-
CSF. 
Continue 
lenalidomide dose. 
Follow CBC. 
Consider G-CSF. 
 
 


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Table 4: Dose modifications for Lenalidomide 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Non-blistering 
rash thought 
related to 
Lenalidomide 
no change in 
dose 
no change in 
dose 
Hold 
lenalidomide. 
If resolves to ≤ 
grade 1 restart 
lenalidomide at 
next lower dose 
level and continue 
through the 
remainder of the 
scheduled 
treatment.  
Omitted doses are 
not made up. 
Discontinue 
lenalidomide.  
Remove patient 
from study. 
Desquamating 
(blistering) rash 
thought related to 
lenalidomide 
 
Discontinue 
lenalidomide.  
Remove patient 
from study 
Discontinue 
lenalidomide.  
Remove patient 
from study 
Discontinue 
lenalidomide.  
Remove patient 
from study 
Discontinue 
lenalidomide.  
Remove patient 
from study 
Neuropathy 
no change in 
dose 
no change in 
dose 
Hold (interrupt) 
lenalidomide. 
If resolves to ≤ 
grade 1, restart 
lenalidomide at 
next lower dose 
level and continue 
through the 
remainder of the 
scheduled 
treatment.  
Omitted doses are 
not made up. 
Discontinue 
lenalidomide.  
Remove patient 
from study. 
Venous thrombosis 
or embolism 
No change in 
dose 
No change in 
dose 
Hold (interrupt) 
lenalidomide and 
start therapeutic 
anticoagulation, if 
appropriate. 
Restart 
lenalidomide at 
investigator’s 
discretion 
(maintain dose 
level). 
Hold (interrupt) 
lenalidomide and 
start therapeutic 
anticoagulation, if 
appropriate. 
Restart 
lenalidomide at 
investigator’s 
discretion 
(maintain dose 
level). 
 
 


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Table 4: Dose modifications for Lenalidomide 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Acute kidney injury 
No change in 
dose 
Decrease 
lenalidomide 
dose by one level 
according to 
Table 3. 
Hold 
lenalidomide. If 
resolves to ≤ 
grade 2, restart 
lenalidomide at 
next lower dose 
level and continue 
through the 
remainder of the 
scheduled 
treatment.  
Omitted doses are 
not made up. 
Hold lenalidomide. 
If resolves to ≤ 
grade 2, restart 
lenalidomide at 
next lower dose 
level and continue 
through the 
remainder of the 
scheduled 
treatment.  
Omitted doses are 
not made up. 
Other clinically 
significant, non-
hematologic 
toxicity thought to 
be related to  
lenalidomide 
No change in 
dose 
No change in 
dose 
Hold 
lenalidomide. If 
resolves to ≤ 
grade 2, restart 
lenalidomide at 
next lower dose 
level and continue 
through the 
remainder of the 
scheduled 
treatment.  
Omitted doses are 
not made up. 
Hold lenalidomide. 
If resolves to ≤ 
grade 2, restart 
lenalidomide at 
next lower dose 
level and continue 
through the 
remainder of the 
scheduled 
treatment.  
Omitted doses are 
not made up. 
 
 
6.3 
Dose Modifications for Mitoxantrone, Etoposide, Cytarabine 
 
Table 5: Dose modifications for mitoxantrone, etoposide, cytarabine 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Nausea 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Vomiting 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Diarrhea 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Neutropenia 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Thrombocytopenia 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Non-blistering 
no change in 
no change in 
no change in dose  no change in dose 


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rash  
dose 
dose 
Table 5: Dose modifications for mitoxantrone, etoposide, cytarabine 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Desquamating 
(blistering) rash  
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Neuropathy 
 
no change in 
dose 
no change in 
dose 
no change in dose 
no change in dose 
Other clinically 
significant non-
hematologic 
toxicity 
no change in 
dose 
no change in 
dose 
Per physician 
discretion or 
institutional 
practice 
Per physician 
discretion or 
institutional 
practice 
 
 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a 
worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, 
including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically 
significant adverse change in the frequency or intensity of a pre-existing condition) should be 
considered an AE. A diagnosis or syndrome should be recorded on the AE page of the CRF 
rather than the individual signs or symptoms of the diagnosis or syndrome.  An overdose, 
accidental or intentional, whether or not it is associated with an AE, or abuse, withdrawal, 
sensitivity or toxicity to an investigational product should be reported as an AE. If an overdose is 
associated with an AE, the overdose and adverse event should be reported as separate terms.  All 
subjects will be monitored for AEs during the study. Assessments may include monitoring of any 
or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, 
radiological or surgical findings, physical examination findings, or findings from other tests 
and/or procedures. 
 
All AEs will be recorded by the Investigator from the first dose of study treatment until 28 days 
after the last dose of lenalidomide and those SAEs made known to the investigator at any time 
thereafter that are suspected of being related to lenalidomide. AEs and serious adverse events 
(SAEs) will be recorded on the AE page of the CRF and in the subject’s source documents. All 
SAEs must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge 
of the event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form. 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 


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Toxicity will be scored using CTCAE Version 4.03 for toxicity and adverse event reporting.  A 
copy of the CTCAE Version 4.03 can be downloaded from the CTEP homepage 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.03.  All 
adverse clinical experiences, whether observed by the investigator or reported by the patient, 
must be recorded, with details about the duration and intensity of each episode, the action taken 
with respect to the test drug, and the patient’s outcome.  The investigator must evaluate each 
adverse experience for its relationship to MEC, relationship to lenalidomide, and for its 
seriousness. The investigator must appraise all abnormal laboratory results for their clinical 
significance.  If any abnormal laboratory result is considered clinically significant, the 
investigator must provide details about the action taken with respect to the test drug and about 
the patient’s outcome. 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and until 28 days after the last dose of study treatment. 
Participants continuing to experience toxicity at the off study visit may be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. 
 
7.1 
Expected Toxicities  
 
7.1.1 Adverse Event List for Mitoxantrone 
 
The most common adverse events include myelosuppression, fever and chills, alopecia, mucositis, 
and nausea and vomiting.  Other commonly reported events include GI bleeding, malaise, fatigue, 
cardiomyopathy, anorexia and weakness. Other adverse events include cardiac arrhythmias, 
bleeding, abdominal pain, hepatitis, cough, shortness of breath, infertility, neuropathy and headache.  
Rare side effects include urticaria, rash, anaphylaxis, extravasation at the IV site, chest pain, 
pneumonitis, second cancers, and tachycardia. 
 
7.1.2 Adverse Event List for Etoposide 
 
The most common side effects are myelosuppression, mucositis, nausea, vomiting, and alopecia.  
Hypotension can occur during administration. Allergic reactions can also occur. Other adverse 
events include facial and tongue swelling, cough, back pain, abdominal pain, fatigue, fever, 
pulmonary fibrosis, rash, and hepatic toxicity. Rare toxicities include second cancers, rash, urticaria, 
itching, constipation, transient cortical blindness, optic neuritis, anaphylaxis, congestive heart 
failure, myocardial infarction, somnolence, and thrombophlebitis. 
 
7.1.3 Adverse Event List for Cytarabine 
 
The most common side effects include myelosuppression, nausea, vomiting, diarrhea, skin rash, 
mucositis, alopecia, fever, and reduced kidney function. Conjunctivitis may also occur. Other 
adverse events include diarrhea, urinary retention, confusion, jaundice, dizziness, and abdominal 
pain. Rare toxicities include pancreatitis, cough, and anaphylaxis. 
 
 


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7.1.4 Adverse Event List for Lenalidomide 
 
Most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: leukopenia, neutropenia, febrile neutropenia, granulocytopenia, 
lymphopenia, pancytopenia, anemia, thrombocytopenia, blurred vision, diarrhea, abdominal 
pain, toothache, constipation, dyspepsia, nausea, vomiting, asthenia, fatigue; edema, pyrexia, 
chills, pneumonia, bronchitis, upper respiratory tract infection, urinary tract infection, erysipelas, 
gastroenteritis, Herpes simplex, Herpes zoster, Influenza, lower respiratory tract infection, 
sinusitis, sepsis, bacteremia, nasopharyngitis, pharyngitis, rhinitis, weight loss; decreased 
appetite, hyperglycemia, hypokalemia, hypocalcemia, hypophosphatemia,  hypomagnesemia, 
hyponatremia, pain in extremity, pain in limb, arthralgia, back pain, bone pain, muscle spasms, 
musculoskeletal pain, muscle cramp, chest pain, myalgia, dizziness, dysgeusia, headache; 
cataracts, hypoaesthesia; neuropathy, peripheral neuropathy, peripheral sensory neuropathy, 
tremor, cough, dyspnea, epistaxis, pulmonary embolism, deep vein thrombosis, dry skin, 
pruritus, rash, hypersensitivity (in uncommon category), depression, insomnia and recently 
vertigo. 
 
Complete and updated adverse events are available in the Investigational Drug Brochure 
 
7.2 
Adverse Event Characteristics 
 
7.2.1 CTCAE term (AE description) and grade 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for AE reporting.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03.  A copy of the CTCAE 
version 4.03 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required 
• Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
• Grade 4 = Life-threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable 
• Grade 5 = Death - the event results in death 
 
7.2.2 Serious Adverse Events  
A serious adverse event (SAE) is any AE occurring at any dose that: 
• Results in death; 


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• Is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate risk 
of death from the AE); 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
• Is a congenital anomaly/birth defect; 
• Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious. 
 
7.2.3 Attribution 
 
The Investigator must determine the causal relationship between the administration of 
lenalidomide, the administration of MEC, and the occurrence of an AE/SAE as Not Related or 
Related as defined below: 
Not Related: Means a causal relationship of the adverse event to IP administration is unlikely or 
remote, or other medications, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 
Related: Means there is a reasonable possibility that the administration of IP caused the adverse 
event. ‘Reasonable possibility’ means there is evidence to suggest a causal relationship between 
the IP and the adverse event. 
Causality should be assessed as per the categories below and provided for every AE/SAE based 
on currently available information. Causality is to be reassessed and provided as additional 
information becomes available. 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment.  
If an event is assessed as possibly, probably or definitely related to a comparator, ancillary or 
additional IP that has not been manufactured or provided by Celgene, please provide the name of 
the manufacturer when reporting the event. 
 
7.2.4 Duration, Action Taken and Outcome 
 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event 


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The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(e.g., discontinuation, interruption, or dose reduction of IP, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
 
The Investigator will report the outcome of the event for both AEs and SAEs.  All SAEs that 
have not resolved upon discontinuation of the subject’s participation in the study must be 
followed until recovered (returned to baseline), recovered with sequelae, not recovered or death 
(due to the SAE). 
 
7.3 
Reporting Requirements for Specific Adverse Events 
 
7.3.1 Abnormal Laboratory Values  
 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• results in discontinuation from the study, and 
• is judged to be of significant clinical importance 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. If a laboratory abnormality is one component 
of a diagnosis or syndrome, then only the diagnosis or syndrome should be recorded on the AE 
page/screen of the CRF. If the abnormality was not a part of a diagnosis or syndrome, then the 
laboratory abnormality should be recorded as the AE. If possible, the laboratory abnormality 
should be recorded as a medical term and not simply as an abnormal laboratory result (e.g., 
record thrombocytopenia rather than decreased platelets). 
 
7.3.2 Second Primary Malignancies 
 
Second primary malignancies will be monitored as events of interest and must be reported as 
serious adverse events the subject is in. This includes any second primary malignancy, regardless 
of causal relationship to study drugs occurring at any time for the duration of the study, from the 
time of signing the ICD for at least 3 years from the date the last subject is enrolled into the 
study. Events of second primary malignancy are to be reported using the SAE report form and 
must be considered an “Important Medical Event” if no other serious criteria apply; these events 
must also be documented in the appropriate page(s) of the CRF (i.e., AE and SPM CRF) and 
subject’s source documents. Documentation on the diagnosis of the second primary malignancy 
must be provided at the time of reporting as a serious adverse event (e.g., any confirmatory 
histology or cytology results, X-rays, CT scans, etc.). 
 
7.3.3 Pregnancies  
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on study treatment, or within 28 
days from last study treatment , are considered immediately reportable events.  Study treatment 
is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to the Coordinating Center for submission to Celgene Drug Safety 


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immediately by facsimile, or other appropriate method, using the Pregnancy Initial Report Form, 
or approved equivalent form. The female subject may be referred to an obstetrician-gynecologist 
(not necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy, and the 
Coordinating Center and Celgene notified immediately about the outcome of the pregnancy 
(either normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form.  
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Celgene immediately by facsimile, or 
other appropriate method, within 24 hours of the Investigator’s knowledge of the event using the 
SAE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking lenalidomide should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. 
 
7.3.4 Overdose  
 
Overdose, as defined for this protocol, refers to chemotherapy drug dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of lenalidomide, mitoxantrone, etoposide, or cytarabine assigned to a given patient, 
regardless of any associated adverse event or sequelae: 
• 
PO-any amount over the protocol-specified dose 
• 
IV-10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency. 
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate. Complete data about drug administration including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report forms. 
 
 
 The Coordinating Center will submit reports of all suspected or confirmed pregnancies, 
pregnancy outcomes, neonatal deaths or overdoses to Celgene Drug Safety immediately by 




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Serious adverse events (SAE) are defined above.  The investigator must inform the Coordinating 
Center in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied to 
Celgene by facsimile within 24 hours.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the investigational 
product(s).  Information not available at the time of the initial report (e.g., an end date for the 
adverse event or laboratory values received after the report) must be documented on a follow-up 
report.  A final report to document resolution of the SAE is required.  The Celgene tracking 
number (RV-CL-AML-PI006779) and the institutional protocol number should be included on 
SAE reports (or on the fax cover letter) sent to Celgene.  A copy of the fax transmission 
confirmation of the SAE report to Celgene should be attached to the SAE and retained with the 
patient records. 
 
The Coordinating Center will submit all SAE reports to Celgene Drug Safety immediately by 
facsimile, or other appropriate methods on behalf of the participating site. 
 
7.4.2 Reporting to the IRB  
 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. In addition to SAEs that meet criteria set forth in Section 7.2.2, the DF/HCC requires 
reporting of any medical event equivalent to an unexpected grade 2 or 3 with a possible, 
probable or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) regardless of 
study phase or attribution. 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.    
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Coordinating Center within the timeframes detailed in the table 
below.  The Coordinating Center will submit AE reports from outside institutions to the DFCI 
OHRS according to DFCI IRB policies and procedures in reporting adverse events.  
 
 
 
 
Attribution 
DF/HCC Reportable AEs 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE Expected 
or Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last intervention, 
the AE should be reported within 1 business day of learning of the event. 
 




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• The administration of blood or platelet transfusion as routine treatment of studied 
Indication.  However, hospitalization or prolonged hospitalization for a complication of 
such transfusion remains a reportable SAE. 
• A procedure for protocol/disease-related investigations (e.g., surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling). However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE. 
• Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• A procedure that is planned (i.e., planned prior to starting of treatment on study); must be 
documented in the source document and the CRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
• An elective treatment of or an elective procedure for a pre-existing condition unrelated to 
the studied indication. 
• Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
 
If an AE is considered serious, both the AE CRF and the SAE Report Form must be completed.  
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to study drugs, action taken regarding study drugs, and outcome. 
 
7.4.5 Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
Celgene shall notify the Investigator via an IND Safety Report of the following information: 
 
• Any AE suspected of being related to the use of drug in this study or in other studies that 
is both serious and unexpected. 
• Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
 
The Investigator shall notify his/her IRB/EC promptly of these new serious and unexpected 
AE(s) or significant risks to subjects. 
 




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myelodysplastic syndromes in vitro.  Lenalidomide causes a delay in tumor growth in some in 
vivo nonclinical hematopoietic tumor models including multiple myeloma. Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma 
cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth 
of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and 
other cell lines without chromosome 5 deletions.   
 
Immunomodulatory properties of lenalidomide include activation of T cells and natural killer 
(NK) cells, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., 
TNF-α and IL-6) by monocytes. Lenalidomide inhibited the secretion of pro-inflammatory 
cytokines and increased the secretion of anti-inflammatory cytokines from peripheral blood 
mononuclear cells.  Lenalidomide inhibited the expression of cyclooxygenase-2 (COX-2) but not 
COX-1 in vitro.  In multiple myeloma cells, the combination of lenalidomide and dexamethasone 
synergizes the inhibition of cell proliferation and the induction of apoptosis. 
 
8.1.2.2 
Absorption  
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose.. However, in 
the pivotal MM and MDS registration trials where the efficacy and safety were established for 
lenalidomide, the drug was administered without regard to food intake. Thus, lenalidomide can 
be administered with or without food.    
 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum 
blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg).  No 
plasma accumulation was observed with multiple daily dosing.  Plasma lenalidomide declined in 
a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 
28 at all 4 doses.  Peak and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg.   (20)  Exposure (AUC) in multiple myeloma patients is 57% higher than 
in healthy male volunteers.  
8.1.2.3 
Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 29% in healthy subjects 
and 23% in MM patients. 
8.1.2.4 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy subjects and 
patients with MM or MDS, approximately 65% to 85% of the administered dose of lenalidomide 
is eliminated unchanged through urinary excretion. The process exceeds the glomerular filtration 
rate and therefore is partially or entirely active.  Half-life of elimination is approximately 3 
hours.  
8.1.3 Form 
 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no charge 
through the REMS® program.  Dosage form Lenalidomide will be supplied as capsules for oral 


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administration. Lenalidomide is an off-white to pale-yellow solid. 
 
8.1.4 Storage and Stability 
 
Lenalidomide will be shipped directly to the participating site.   Bottles will contain a sufficient 
number of capsules for one cycle of dosing (10 days).   Lenalidomide should be stored at room 
temperature away from direct sunlight and protected from excessive heat and cold.  
 
8.1.5 Compatibility 
 
Lenalidomide is compatible with the chemotherapy drugs and supportive care drugs as outlined 
in the protocol. Additional questions not contained within this protocol may also be investigated 
by referencing the investigator’s brochure.   
 
8.1.6 Handling 
 
Females of childbearing potential should not handle or administer lenalidomide unless they are 
wearing gloves. 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
8.1.7 Availability 
 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Lenalidomide will be 
provided in accordance with the REMS® program of Celgene Corporation.  
     
8.1.8 Preparation 
 
Lenalidomide will be supplied in oral formulation. No on site preparation is needed. 
Lenalidomide will be shipped directly to the participating site. Bottles will contain a sufficient 
number of capsules for one cycle of dosing.    
 
8.1.9 Administration 
 
Dosing should be taken at approximately the same time each day and is recommended to be 
given in the morning.  If a dose of lenalidomide is missed, it should be taken as soon as possible 
on the same day (until midnight).  If it is missed for the entire day, it should not be made up. 
Vomited doses will not be made up. Patient may take lenalidomide with or without food. 
Lenalidomide should be administered prior to other chemotherapy on a given day. 
 
Patients who take more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately. 
 


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8.1.10 Ordering 
 
Lenalidomide (Revlimid®) will be provided to research subjects for the duration of their 
participation in this trial at no charge to them or their insurance providers.  Celgene Corporation 
will supply Revlimid® (lenalidomide) to study participants at no charge through Celgene’s 
Revlimid Risk Evaluation and Mitigation Strategy® (REMS) (formerly known as RevAssist® 
Program).  Lenalidomide will be provided in accordance with Celgene Corporation’s Revlimid 
REMS® program.  Per standard Revlimid REMS® program requirements,  all physicians who 
prescribe lenalidomide for research subjects enrolled into this trial, and all research subjects 
enrolled into this trial, must be registered in, and must comply with, all requirements of the 
Revlimid REMS®program.   
 
Further information about the Revlimid REMS® program is available at 
www.celgeneriskmanagement.com. 
 
Drug will be shipped on a per patient basis by the contract pharmacy to the participating site. The 
treatment will be shipped directly to the research pharmacy for distribution to the patient. Only 
enough lenalidomide for one cycle of therapy will be supplied to the patient each cycle. 
 
8.1.11 Accountability 
 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received, and comparing it with the accompanying study drug accountability form.  The 
Investigator will verify the accuracy of the information on the form, sign and date it, retain a 
copy in the study file, and return a copy to Celgene or its representative.  The investigator, or a 
responsible party designated by the investigator, should maintain a careful record of the 
inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF) 
or another comparable drug accountability form.  (See the NCI Investigator’s Handbook for 
Procedures for Drug Accountability and Storage.) 
 
8.1.12 Destruction and Return 
 
Celgene will instruct the Investigator on the return or destruction of unused study drug.  If any 
study drug is lost or damaged, its disposition should be documented in the source documents.  
Study drug supplies will be retained at the clinical site pending instructions for disposition by 
Celgene.  Patients will be instructed to return empty bottles or unused capsules to the clinic site 
 
8.2 
Mitoxantrone 
 
8.2.1 Description 
 
Mitoxantrone is a synthetic antineoplastic anthracenedione for intravenous use.  It is a DNA-
reactive agent that intercalates into deoxyribonucleic acid (DNA) through hydrogen bonding, 
causing cross links and strand breaks.  Mitoxantrone also interferes with ribonucleic acid (RNA) 
and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing 
damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human 


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cells. Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation 
and to impair antigen presentation. 
 
8.2.2 Form 
 
Mitoxantrone Injection, USP (concentrate) is a sterile aqueous solution containing Mitoxantrone 
hydrochloride at a concentration equivalent to 2 mg Mitoxantrone free base per ml supplied in 
vials for multiuse dose. 
 
8.2.3 Storage and Stability 
 
Store between 20 to 25 degrees C. Do not freeze.  Opened vials may be stored at room 
temperature for 7 days or under refrigeration for up to 14 days. Solutions diluted for 
administration are stable for up to 7 days at room temperature or under refrigeration. 
 
8.2.4 Compatibility 
 
Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form. 
Because specific compatibility data is not available, mitoxantrone should not be mixed in the 
same infusion with other drugs. 
 
8.2.5 Handling 
 
Skin accidentally exposed to Mitoxantrone should be rinsed copiously with warm water and if 
the eyes are involved, standard irrigation techniques should be used immediately. Procedure for 
proper handling and disposal of anticancer drugs should be followed.    
 
8.2.6 Availability 
 
Mitoxantrone is commercially available.  It is supplied by APP Pharmaceuticals.  It will not be 
provided for this study. 
 
8.2.7 Preparation 
 
Mitoxantrone is supplied as concentrate that must be diluted prior to injection. The dose of 
mitoxantrone should be diluted to at least 50 ml with either 0.9% Sodium Chloride Injection 
(USP) or 5% Dextrose Injection (USP). Mitoxantrone may be further diluted into Dextrose 5% in 
Water, Normal Saline, or Dextrose 5% with Normal Saline and used immediately. Product 
should be visually inspected for particulate matter and discoloration whenever solution and 
container permit. 
 
8.2.8 Administration 
 
Mitoxantrone should be given by intravenous infusion over approximately 6-10 minutes. Severe 
local tissue damage may occur if there is extravasation. The tubing should be attached to a 
butterfly needle or other suitable device and inserted preferably into a large vein. If any signs or 
symptoms of extravasation have occurred, including burning, pain, pruritus¸ erythema, swelling, 


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blue discoloration¸ or ulceration, the injection or infusion should be immediately terminated and 
started in another vein. 
 
8.2.9 Ordering 
 
Mitoxantrone is commercially available.  It will be ordered by the oncology attending and 
supplied via the inpatient oncology pharmacy per institutional guidelines. 
 
8.2.10 Accountability 
 
Mitoxantrone accountability will be handled via institutional chemotherapy policies. 
 
8.2.11 Destruction and Return 
 
N/A or handled via institutional chemotherapy policies 
 
8.3 
Etoposide  
 
8.3.1 Description 
 
Etoposide is used in the treatment of certain neoplastic diseases.  It is a 4’- 
demethylepipodophyllotoxin 9-(4, 6-0-(R)-ethylidene-B-D-glucopyranoside). It is very soluble 
in methanol and chloroform, slightly soluble in ethanol and sparingly soluble in water and ether.  
Its main effect appears to be at the G2 portion of the cell cycle in mammalian cells. The 
predominant macromolecular effect of etoposide appears to be the induction of DNA strand 
breaks by an interaction with DNA topoisomerase II on the formation of free radicals. 
 
8.3.2 Form 
 
Etoposide Injection USP is available in 100 mg(5ml) and 250 mg(12.5ml) sterile, multiple dose 
vials. The pH of the clear, colorless to pale yellow solution is 3 to 4. Each ml contains 20 mg 
Etoposide, 2 mg anhydrous citric acid, 30 mg benzyl alcohol, 80 mg polysorbate, 650 mg 
polyethylene glycol, and 30.5 percent (v/v) dehydrated alcohol.   
 
8.3.3 Storage and Stability 
 
Unopened vials of Etoposide Injection USP are stable for 24 months at room temperature. Vials 
diluted as recommended to a concentration of 0.2 or 0.4 mg/ml are stable for 96 and 24 hours, 
respectively, at room temperature under normal room fluorescent light in both glass and plastic 
containers. 
 
8.3.4 Compatibility 
 
Because specific compatibility data is not available, etoposide should not be mixed in the same 
infusion with other drugs. 
 


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8.3.5 Handling 
 
Procedures for proper handling and disposal should follow institutional guidelines. If Etoposide 
solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and 
water and flush the mucosa with water. 
 
8.3.6 Availability 
 
Etoposide is commercially available and will not be provided for this study. It is supplied at 
100mg/5ml and 250 mg/12.5 multiple dose vials. 
 
8.3.7 Preparation 
 
Etoposide Injection USP must be diluted prior to use with either 5% Dextrose Injection or 0.9% 
Sodium Chloride Injection, to give a final concentration of 0.2 to 0.4 mg/ml or per institutional 
standard. If solutions are prepared at concentrations above 0.4 mg/ml, precipitation may occur. 
 
8.3.8 Administration 
 
Hypotension following rapid intravenous administration has been reported; hence, it is 
recommended that the Etoposide solution be administered over a 30-60 minute period. A longer 
duration of administration may be used if the volume of fluid to be infused is a concern. 
Etoposide should not be given by rapid intravenous injection. The bag of etoposide should be 
inspected prior to administration and held if the solution is cloudy or precipitated drug is 
observed. 
 
8.3.9 Ordering 
 
Etoposide is commercially available.  It will be ordered and supplied per institutional guidelines. 
 
8.3.10 Accountability 
 
Etoposide accountability will be handled via institutional chemotherapy policies. 
 
8.3.11 Destruction and Return 
 
N/A or handled via institutional chemotherapy policies. 
 
8.4 
Cytarabine 
 
8.4.1 Description 
 
Cytarabine (1-beta-D-arabinofuranosylcytosine) is a synthetic antineoplastic agent. The exact 
mechanism of action for cytarabine is unknown. It is thought that the drug is an antimetabolite, 
interfering with the synthesis of deoxyribonucleic acid (DNA). The inhibition of the conversion 
of cytidine to deoxycytidine is the presumed primary site of action. Cytarabine may be 
incorporated into DNA and RNA as in vitro chromosome breaks have been associated with the 


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drug, and the clinical effects are limited to tissues with a high rate of cellular proliferation. 
Alternatively, cytarabine may have a differentiating role rather than an antimitotic effect as the 
mechanism of action. Cytarabine reportedly also has immunosuppressive activity. Two important 
properties of cytarabine include: 
 
o A relatively unique synergistic effect with other classes of drugs including alkylating 
agents, thiopurines, and anthracycline antibiotics. 
 
o Clinical effectiveness that is significantly affected by the schedule of administration. 
Cytarabine is effective for refractory leukemia and the addition of anthracyclines may 
enhance this effect. 
 
8.4.2 Form 
 
Cytarabine (Cytosar-U, Cytosine Arabinoside, Ara-C) for Injection, USP, is a sterile lyophilized 
material for reconstitution. It is available in multi-dose vials containing 100  mg, 500 mg, 1 g or 
2 g sterile cytarabine. Cytarabine is commercially available and will not be provided for this 
study. 
 
8.4.3 Storage and Stability 
 
Cytarabine lyophilized powder should be stored at 150  to 300 C. Solutions reconstituted with 
Bacteriostatic Water for Injection with Benzyl Alcohol to 0.945% weight/volume may be stored 
at 150  to 300 C for up to 48 hours. The pH of the reconstituted solution is about 5. Solutions with 
a slight haze should be discarded. Solutions reconstituted with a preservative should be used 
immediately. Undiluted vials should be stored at room temperature. Reconstituted solutions are 
stable for 7 days at room temperature. 
 
8.4.4 Compatibility 
 
For intravenous cytarabine administration, cytarabine lyophilized powder should be reconstituted 
with Bacteriostatic Water for Injection with Benzyl Alcohol 0.945% weight/volume. 
 
8.4.5 Handling 
 
Cytarabine is manufactured by the Upjohn Company in Kalamazoo, MI, USA. Cytarabine is 
commercially available. Procedures for proper handling and disposal should follow institutional 
guidelines. 
 
8.4.6 Availability 
 
Cytarabine is commercially available and will not be provided for this study.  
 
8.4.7 Preparation 
 
Cytarabine should be reconstituted according to institutional standard; recommendations for 
reconstitution in Bacteriostatic Water for Injection with Benzyl Alcohol 0.945% weight/volume 


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as a diluent as follows are provided below: 
 
Vial lyophilized dose (mg) 
Bacteriostatic Water for 
Injection with Benzyl 
Alcohol 0.945% (ml) 
Final Cytarabine 
Concentration (mg/ml) 
100 
5 
50 
500 
10 
50 
1000 
10 
100 
2000 
20 
100 
 
8.4.8 Administration 
 
Cytarabine is administered intravenously, over approximately one hour. Cytarabine injection 
may induce hyperuricemia secondary to rapid lysis of leukemia cells.  Periodic checks of bone 
marrow, liver and kidney functions should be performed in patients receiving cytarabine. 
 
8.4.9 Ordering 
 
Cytarabine is commercially available.  It will be ordered and supplied per institutional 
guidelines. 
 
8.4.10 Accountability 
 
Cytarabine accountability will be handled via institutional chemotherapy policies. 
 
8.4.11 Destruction and Return 
 
N/A or handled via institutional chemotherapy policies. 
 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Correlative studies are optional. Patients who consent will have a purple top tube sent as standard 
of care for NGS molecular testing according to site SOC (e.g.,  Rapid Heme Panel, Heme 
SNaPshot assay) testing at the time of study entry, and subsequent bone marrows as clinically 
indicated. Missed samples due to weekends, holidays, insufficient volume or patient refusal will 
not be considered violations.  Additional DNA will be stored for future testing, in the event of 
new genetic mutations. 
 
9.1 
Laboratory Correlative Studies 
 
CORRELATIVE STUDY 1: Understanding the leukemia genetics of relapsed and 
refractory AML. 
 
Acute myeloid leukemia (AML) is a disease characterized by the combinatorial action of 
multiple somatic mutations that lead to an arrest in normal hematopoietic differentiation and 
uncontrolled growth of immature bone marrow myeloid blasts (55,56). Advances in gene 


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sequencing technology over the past decade have allowed for the identification of over 50 
recurrent mutations in AML patients. Mutational testing of a limited number of genes is already 
considered an integral part of standard clinical practice. In myelodysplasia, a related myeloid 
disease, the finding of isolated deletion of 5q is an approved indication for the use of 
lenalidomide (57). Individual mutations can be associated with sensitivity to specific therapies 
and the development of resistance. For instance, mutations in TP53 along with loss of 
chromosome 5q have been demonstrated to predict a poor response to treatment with 
lenalidomide (58). Recent work has also demonstrated that MDS clonal structure is dynamic 
during treatment with lenalidomide as some initially dominant clones disappear and founder 
clones tend to become dominant over time (59,60). Understanding these changes and how they 
relate to treatment response is an important next step in finding predictive markers to identify 
appropriate patients for selected therapies. In order to address these issues in this study of 
salvage chemotherapy combined with lenalidomide we plan to sequence recurrently mutated 
genes in myeloid malignancies using standard sequencing panels available at the institutions 
involved in the trial, such as the Heme SNaPshot assay available at Massachusetts General 
Hospital, and the Rapid Heme Panel assay at the Brigham and Women’s Hospital Center for 
Advanced Molecular Diagnostics (CAMD). Sequencing using one of these assays or a similar 
assay is recommended at clinical trial enrollment, and then on subsequent bone marrows as 
clinically indicated. This assay can be performed from a single purple top tube collected from a 
bone marrow aspirate or per local SOP.  
 
9.1.1.1 
Collection of Specimen(s) 
Collection of these samples is optional but recommended. A purple top tube of bone marrow 
aspirate (or other appropriate tube based on the assay) will be collected from each consenting 
patient: at study enrollment; the day + 35 (+/-3 days) bone marrow biopsy if indicated or at count 
recovery if sooner;); as well as at relapse, if this occurs. For this correlative, the baseline 
mutation testing may be performed at the time of relapse and may occur up to 2 months prior to 
enrollment as part of clinical care, provided that no intervening therapy has been given except 
hydroxyurea or 6MP. If it cannot be obtained off the bone marrow, a sample using leukemic 
blood will be adequate. 
 
9.1.1.2 
Handling and Shipping of Specimens 
 
• Sequencing and any sample shipping will be performed locally according to standard of 
care at each local institution.  
 
CORRELATIVE STUDY 2: Assessing lenalidomide function in AML. 
 
In myelodysplasia, a related myeloid disease, the finding of isolated deletion of 5q is an 
approved indication for the use of lenalidomide. This sensitivity to lenalidomide is mediated 
through selective proteosomal degradation CSNK1A1, a haploinsufficient gene found in the 
commonly deleted region of 5q. Lenalidomide induces degradation by binding to the E3 
ubiquitin ligase cereblon thus altering its affinity for some targets such as CSNK1A1 and leading 
to its ubiquitination and eventual degradation. In multiple myeloma, another disease in which 
lenalidomide is approved, the proteins targeted for degradation are IKZF1 and IKZF3, which are 
crucial B-cell transcription factors. In both diseases, the genes targeted by lenalidomide show 


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decreased protein levels but no alteration in the RNA level. Therefore, the only way to assess this 
function of lenalidomide is through direct measurement of protein levels. In multiple myeloma, 
sensitivity to lenalidomide has been associated with the protein levels of cereblon and its 
associated complex.  
 
Understanding whether these previously identified targets are also degraded in AML and 
whether cereblon levels might predict response to lenalidomide is important for understanding its 
mechanism of action in AML. We have previously used mass spectrometry to measure the levels 
of cereblon and lenalidomide targets in cell lysates. We propose to collect samples before and 
after treatment with lenalidomide to measure the levels of target proteins. 
Peripheral blood and bone marrow will be collected at the following time points: 
 
• Study enrollment, prior to initiation of treatment: 5ml peripheral blood and 2ml bone 
marrow aspirate 
• On day 4, prior to initiation of MEC chemotherapy, a 5ml peripheral blood sample will 
be collected. This may be obtained before or after the dose of lenalidomide that day. 
• Day +35+/- 3 days (or at count recovery if sooner): 5ml peripheral blood and 2ml bone 
marrow aspirate (at the time of marrow assessment) 
 
This correlative study is recommended but optional. Study samples will be collected and 
processed according to local tissue banking protocols.  
 
MGH: patient samples will be collected and stored using the local tissue bank prior to analysis.  
  
BWH/DFCI: patient samples will be collected and stored using the local tissue bank prior to 
analysis. 
  
BIDMC: patient samples will be collected and stored using the local tissue bank prior to analysis. 
  
UVA: patient samples will be collected and stored using the local tissue bank prior to analysis. 
 
CORRELATIVE STUDY 3: Assessing the impact of therapy on tumor-reactive T-cells 
 
In the phase I study on Lenalidomide and MEC, we found that exposure to this chemotherapy 
combination results in the expansion of IFN-ɣ expressing T-cells when exposed to leukemia cell 
lysate from the time of relapse. Using leukemia cells collected at baseline, when T-cells from 
pre-treatment and then at the end of therapy are exposed to the leukemia cell lysate, we saw a 
significant increase in the number of reactive T-cells following MEC and Lenalidomide. At the 
peak following MEC and lenalidomide therapy, there was a mean 3.8-fold and 7.5-fold increase 
in the level of IFN-γ expressing CD4+ and CD8+ T cells in the peripheral blood, respectively, 
consistent with the expansion of tumor-reactive T-cells. We therefore propose an optional 
correlative study to collect bone marrow and peripheral blood samples at diagnosis and at 
response to further evaluate the development of a leukemia-specific T-cell response after 
exposure to leukemia cells. 
 
Blood and bone marrow specimens should be collected in heparinized tubes (large green top 






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Boston-02215 
 
If possible, as samples are being prepared, contact Shruti Bhatt at 
 
 
 
10. 
STUDY CALENDAR 
 
10.1 
Pre-Treatment Evaluations 
 
All required tests must be performed within 21 days of the start of treatment. 
Clinical Evaluations: 
1. A complete history with full details of the patient’s previous treatment and response 
will be obtained.  
2. A complete physical examination.  
3. Marrow aspiration and biopsy with cytogenetics, flow cytometry, and molecular 
genetic NGS sequencing panel (e.g. “heme snapshot” or “rapid heme” panel, per local 
site). Patients are eligible who have a dry aspirate. 
4. Echocardiogram or MUGA to assess ejection fraction. 
5. Chest X-ray 
6. Performance Status 
7. All study participants must be registered into the mandatory REMS program, and 
be willing and able to comply with the requirements of REMS. 
Laboratory Evaluations: 
1. CBC with differential 
2. Comprehensive chemistry profile, including measures of hepatic and renal function, 
such as electrolytes, BUN, creatinine, alkaline phosphate, bilirubin, and 
transaminases, as per institutional guidelines.   
3. Pregnancy Test (serum or urine) in child bearing female. Refer to inclusion criteria 
3.1.13 for details. 
 
10.2 
Bone Marrow Assessments 
 
All patients will have bone marrow examined at the time of count recovery or, if counts have not 
yet recovered, at Day +35 +/- 3 days. Patients with persistent leukemia will be followed for 
overall survival as noted in section 10.4. 
 
Patients who have count recovery within one week of the Day 35 marrow do not need a repeat 
bone marrow.  Patients who have not experienced count recovery by Day 45 will have a marrow 
evaluation performed at Day 45+/-3 days regardless of counts.  Patients may have additional 
bone marrows performed as clinically indicated. 
 
10.3 
Post Treatment Evaluations 
 
Standard post-treatment testing, including complete blood counts and, serum chemistries will be 


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performed per institutional guidelines and consistent with clinical good practice. Suggested practice 
would be to perform three times weekly. 
 
10.4 
Long Term Follow Up 
 
Participants will be followed for at least 50 days after the start of protocol treatment to assess for 
response to treatment and adverse events. At the completion of the study treatment, participants 
will be followed for relapse and overall survival outcomes for a total of 3 years from the start of 
treatment. These outcomes should be assessed at approximately 3 months after treatment, and 
then approximately every six months until the 3 year follow-up has been reached. 
 
Patients removed from the study treatment early, for instance patients with refractory disease 
who go onto another therapy within 45 days of the study therapy, and will continue to be 
followed for relapse and survival for up to three years following initiation of study treatment. 
 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. They will then also be followed at the above 
approximate intervals for relapse and survival outcomes. 
 
Baseline evaluations are to be conducted within 21 days prior to the start of protocol therapy.   
 
Assessments must be performed prior to administration of any study agent. Study assessments 
should be administered within + 3 days of the protocol-specified date, unless otherwise noted. 
 
 
Table 6. Required Study Data. 
 
Pre-
treatment 
(within 21 
days) 
Weekly 
(+/-3 
days) 
Count 
recovery or 
Day +35 
(+/- 3 days) 
Day +38 
Day +45 +/-
3days 
Medical History and Physical 
Exam 
X 
 
 
 
 
CBC with diff 
 
X 
X (Diff 
optional) 
 
 
 
X 
Comprehensive chemistry with 
renal and liver functions1 
X 
 
X 
 
 
X 
ABO/Rh 
X 
 
 
 
X 
Bone marrow biopsy and 
aspirate2 
 
X 
 
X 
 
 
X 
Informed Consent 
X 
 
 
 
 
History and physical 
X 
X 
 
 
X 
Performance Status 
X 
 
 
 
 
EKG 
X 
 
 
 
 
MUGA or ECHO 
X 
 
 
 
 


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53 
 
Chest x-ray 
X 
 
 
 
 
Toxicity assessment4 
X 
ongoing throughout 
Enroll in REMS 
X 
 
 
 
 
Pregnancy Test 
Child Bearing Female 
X 
 
 
X 
 
Optional Research Studies 
X5 
b 
X 
 
 
 
1 Chemistry testing to include creatinine, eGFR, BUN, potassium, sodium, chloride, HCO3, glucose, magnesium, 
phosphorus, calcium. Liver function testing to include ALT, AST, total bilirubin, alkaline phosphatase, albumin. 
2 All patients will have bone marrow examined at count recovery or at Day +35 +/- 3 days. Patient will be off 
treatment if persistent leukemia or need for further treatment.  Patients who have count recovery within one week of 
the Day 35 marrow do not need a repeat bone marrow. Patients who have not experienced count recovery by Day 45 
will have marrow at Day 45+/-3 days regardless of counts.  Patients may have additional bone marrows performed 
as clinically indicated. 
3The day 4 peripheral blood research sample should be obtained prior to the initiation of MEC chemotherapy (may 
be obtained before or after lenalidomide on that day). 
4 Toxicity will be assessed from the time of first dose of study treatment through 30 days past the last dose of study 
treatment. 
5Molecular testing (correlative 1) may be performed at the time of disease relapse and within 2 months of study 
enrollment, provided no intervening systemic chemotherapy has been administered (excluding hydroxyurea or 
6MP). 
bSamples for optional correlative 4 may be collected at baseline prior to chemotherapy, and on day 3 of treatment (or 
day 2 or 4 if on a weekend, but prior to MEC administration). 
 
  
11. 
MEASUREMENT OF EFFECT 
 
11.1 
Count Recovery 
 
11.1.1 Time to Neutrophil Recovery 
 
The time to neutrophil engraftment is defined as the first 3 consecutive days of absolute 
neutrophil count >500. 
 
11.1.2 Time to Platelet Recovery 
 
Platelet recovery is defined as a platelet count ≥ 20,000/µL for three consecutive measurements 
over three or more days.  The first of the three days will be designated the day of platelet 
engraftment.  Subjects must not have had platelet transfusions during the preceding 3 days or in 
the following 7 days after the day of engraftment, unless the platelet transfusion is being given 
specifically to achieve a platelet threshold to allow an elective invasive procedure, such as a 
central catheter removal.  The time to a platelet count ≥ 100,000/µL will be collected as well. 
 
11.2 
Treatment-related Mortality 
 
All deaths in the absence of relapse of the primary malignancy will be considered treatment 


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54 
 
related mortality.  The cumulative incidence of treatment related mortality at 50 days will be 
measured. 
 
11.3 
Relapse-Free and Overall Survival 
 
Both overall survival and relapse-free survival will be assessed at 45 days after the start of study 
treatment, as well as over the 3 year planned follow-up period. Overall survival is defined as 
time from diagnosis of disease until date of death or censored on the last known date alive if 
patients are still alive. Testing for recurrent malignancy in the blood, marrow or other sites will 
be used to assess relapse after treatment. Relapse is defined by morphological evidence of the 
original malignancy consistent with pre-treatment features.  Minimal residual disease is defined 
by the sole evidence of malignant cells by flow cytometry, or fluorescent in situ hybridization 
(FISH), or polymerase chain reaction (PCR), or other techniques, in absence of morphological or 
cytogenetic evidence of disease in blood or marrow.  Since the frequency of testing for minimal 
residual disease is highly variable, and the sensitivity is highly variable among laboratory 
techniques, evidence of minimal residual disease will not be sufficient to meet the definition of 
relapse in the context of this study.  Relapse free survival is defined from time of diagnosis to 
disease relapse or death whichever occurs first or censored on the last known date of free from 
disease relapse. 
 
11.4 
Second Malignancies 
 
Patients will be followed for the development of second cancers, including lymphoproliferative 
disorder and myelodysplasia/myeloproliferative disorder. See Section 7.3.2 
 
11.5 
Evaluation of Response 
 
All participants included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each participant should be 
assigned one of the following categories: 1) complete remission, 2) complete remission without 
neutrophil or platelet recovery, 3) persistent disease, 4) early death from leukemia 5) early death 
from toxicity, or 6) unknown (not assessable, insufficient data). World Health Organization 
(WHO) criteria will be used to assess response. Patients will be assessed for complete remission 
or complete remission without platelet recovery per WHO criteria. (43) Patients who experience 
toxicity but die with persistent leukemia will be classified as 3) death of persistent disease. 
 
Morphologic Complete Remission (CR): 
Defined as morphologic leukemia-free state, including <5% blasts in Bone Marrow aspirate with 
marrow spicules, no persistent extramedullary disease, ANC >1000/mm3 and platelet count 
>100,000/mm3. 
 
Morphologic Complete Remission without neutrophil (CRi) or platelet recovery (CRp):  
Defined as CR with the exception of neutrophil count < 1,000/mm3 (CRi) or platelet count < 
100,000/mm3 (CRp). 
 
Persistent Disease:  
Greater than 5% blasts in the marrow. 


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55 
 
 
Recurrence/morphologic relapse:  
Defined as reappearance of >5% blasts in the bone marrow, not attributable to any other cause, 
after the documentation of complete remission (CR) 
 
Early death from leukemia: 
Defined as death within 50 days of treatment attributed to persistent leukemia. 
 
Early death from toxicity: 
Defined as death within 50 days of start of treatment attributed to therapy in the absence of 
leukemia. 
 
11.6 
Transfusion Requirements 
 
Patients will receive transfusion support per institutional guidelines. The number of red blood 
cell and platelet transfusions needed in the first 50 days of treatment will be assessed. 
 
 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data 
for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Participating sites within are responsible for submitting data and/or data forms to the ODQ 
according to the schedule set by ODQ. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; any 


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56 
 
response information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
12.3 
Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix B. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters 
or Safety Reports to all participating institutions for submission to their individual IRBs 
for action as required. 
 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 
12.4 
Collaborative Agreements Language 
 
N/A 
 
13. 
STATISTICAL CONSIDERATIONS 
 
Primary objective 
This is a single arm study to evaluate the efficacy of lenalidomide in combination with 
reinduction chemotherapy (mitoxantrone/etoposide/cytarabine) for patients with relapsed or 
refractory AML.  
 
Sample size  
The primary endpoint is complete remission (CR) and CRp after MEC+lenalidomide. A 45% 
complete remission rate will be considered clinically significant.  The response evaluation will 
be assessed after the first (and only) cycle of treatment. There is no retreatment as a part of this 
protocol. We will plan to evaluate patients who receive the study treatment; we will plan to 
replace up to 2 patients who are not able to complete the ten days of therapy. 
 
A two-stage design is considered here.  A total number of 40 patients is needed in order to detect 
a 20% response rate increase, assuming the null hypothesis is 25%, with a 90% power and 9% 
one-sided type I error rate.  The study will be reevaluated if 4 or fewer responses out of 18 
patients are observed and the treatment will be declared inactive if fewer than 14 responses are 
seen in the total 40 patients. Factors during treatment, such as the rate of treatment completion, 
may be considered in evaluating any responses. The probability of stopping at the first stage is 
0.52, if the true response rate is 25%.   
 


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57 
 
We chose this study design over other possible phase II study designs, including randomized 
phase II designs, because it is powered toward identifying a clinically significant improvement in 
response (20% increase compared to historical rates); a smaller randomized study may be 
underpowered to identify the true response rate. 
 
Primary analysis 
The rate of CR+CRp will be calculated along with the corresponding 90% two-stage exact 
binomial CI.  
 
The analyses for secondary objectives will be descriptive in nature.  Proportion of patients with 
ANC recovery/platelet recovery (as defined in Section 11.1) will be reported, along with median 
days to counts recovery. Total transfusion requirements will be reported as the median and range 
of each blood product. Cumulative incidence of treatment related mortality (defined in Section 
11.2) will be estimated using relapse and early death from relapse as competing risks.   Overall 
survival and Relapse-free survival (defined in Section 11.3) will be estimated using the Kaplan-
Meier method. 
 
Participants who never start protocol therapy, or who do not complete the 10 days of protocol 
based chemotherapy will be excluded from the analyses and will be replaced.  The estimated 
accrual period is 2.5 years. 
 
13.1.1  Evaluation of toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment up until day 
50 or the initiation of other therapy. In the phase I study of 35 patients, 3 dose limiting toxicities 
were noted due to prolonged count recovery. In the current study, we will monitor for toxicities 
and assess them as a part of the two stage design described above. If, within the first 10 patients 
on study, 3 or more experience prolonged neutrophil or platelet recovery beyond day 45 in the 
absence of disease, or other unacceptable toxicities felt related to the study regimen, we will put 
the study on hold to investigate further enrollment. The probability of putting the study on hold 
is 7%, if the true probability of delayed count recovery is 10%. 
 
13.1.2 Evaluation of the Primary Efficacy Endpoint 
 
Analyses will be performed on an intent-to-treat basis. Specifically, all eligible participants, 
except those who are removed and replaced, who are then included in the study, will be assessed 
for response/outcome to therapy, even if there are major protocol therapy deviations.   
 
14. 
PUBLICATION PLAN 
 
The results should be made public within 18 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


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58 
 
 
 


DF/HCC Protocol #: 16-574 
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59 
 
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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DFCI IRB Protocol #: 16-574 
 
 
 
 
 
APPENDIX B 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Version Date: 2/27/19 
 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION .............................................................................................................66 
1.1 
Purpose ...................................................................................................................66 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................66 
2. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................67 
2.1 
DF/HCC Sponsor ...................................................................................................67 
2.2 
Coordinating Center ...............................................................................................68 
2.3 
Participating Institution ..........................................................................................68 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................69 
3.1 
Protocol Distribution ..............................................................................................69 
3.2 
Protocol Revisions and Closures ...........................................................................69 
3.3 
Informed Consent Requirements ...........................................................................70 
3.4 
IRB Documentation ...............................................................................................70 
3.5 
IRB Re-Approval ...................................................................................................70 
3.6 
Participant Confidentiality and Authorization Statement ......................................71 
3.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................71 
3.8 
DF/HCC Protocol Case Number ............................................................................72 
3.9 
Safety Assessments and Toxicity Monitoring .......................................................73 
3.10 
Data Management ..................................................................................................74 
4. 
REQUISITIONING INVESTIGATIONAL DRUG..........................................................74 
5. 
MONITORING: QUALITY CONTROL ..........................................................................75 
5.1 
Ongoing Monitoring of Protocol Compliance .......................................................75 
5.2 
Monitoring Reports ................................................................................................76 
5.3 
Accrual Monitoring ................................................................................................76 
6. 
AUDITING: QUALITY ASSURANCE ...........................................................................76 
6.1 
Audit Plan: NCI Sponsored Trials .........................................................................77 
6.2 
DF/HCC Internal Audits ........................................................................................77 
6.3 
Audit Notifications.................................................................................................77 
6.4 
Audit Reports .........................................................................................................77 
6.5 
Participating Institution Performance ....................................................................77 
 
 
 


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1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF.HCC clinical trial. 
 
1.1 
Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel 
Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and 
Women’s Hospital (BWH)) responsible for the coordination, development, submission, and 
approval of a protocol as well as its subsequent amendments per the DFCI IRB and 
applicable regulatory guidelines (CTEP, Food and Drug Administration (FDA), Office of 
Biotechnology Activities (OBA) etc.).  The Lead Institution is typically the home of the 
DF/HCC Sponsor. The Lead Institution also typically serves as the Coordinating Center for 
the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who takes 
responsibility for initiation, management and conduct of the protocol at all research 
locations. In applicable protocols, the DF/HCC Sponsor will serve as the single liaison with 
any regulatory agencies. The DF/HCC Sponsor has ultimate authority over the protocol and 
is responsible for the conduct of the study at DF/HCC and all Participating Institutions. In 
most cases the DF/HCC Sponsor is the same person as the DF/HCC Overall Principal 
Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC 
Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor as having 
the ultimate authority and responsibility for the overall conduct of the study.    
 
Coordinating Center: The entity that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 


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document and DSMP, and as specified in applicable regulatory guidelines. In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within 
DF/HCC responsible for providing a comprehensive data management platform for 
managing clinical trial data. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities:  
 
2.1 
DF/HCC Sponsor 
 
The DF/HCC Sponsor, Andrew Brunner, M.D., will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training and/or a Site Initiation Visit prior to enrolling participants 
and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. CTEP, FDA, OBA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with the FDA (investigator-held IND trials) as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site. 


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• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
2.2 
Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS). 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Review and approve Participating Site informed consent forms 
• Conduct and document initial and ongoing protocol training 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation and cumulative reports of Serious Adverse Event (SAE) 
reports and Deviations/Violations across all sites and provide to the DF/HCC 
Sponsor for timely review and submission to the DFCI IRB, as necessary.  
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements 
that they will be expected to comply with. 
 
• Carry out approved protocol monitoring plan either by on-site or remote monitoring.  
• Maintain essential regulatory documents of all Participating Institutions which 
includes but is not limited to the following: local IRB approvals/notifications from 
all Participating Institutions, confirmation of Federalwide Assurances (FWAs) for 
all sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites, and protocol training documentation 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.3 
Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited 
to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 


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• Participate in protocol training prior to enrolling participants and throughout the trial 
as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Adverse Event (SAE) reports to local IRB per institutional requirements and 
to the Coordinating Center, in accordance with DF/HCC or other sponsor 
requirements.  
• Submit protocol deviations and violations to local IRB per institutional requirements 
and to the DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 
Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 
Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB approved 
and implemented within 90 days from receipt of the notification. 
 
• Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 


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• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating Center. 
Closures and holds will be effective immediately.  In addition, the Coordinating 
Center, will update the Participating Institutions on an ongoing basis about protocol 
accrual data so that they will be aware of imminent protocol closures. 
 
3.3 
Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form for 
therapeutic protocols. Participating institutions must follow the DF/HCC requirement that 
for all interventional drug, biologic, or device research, only attending physicians may 
obtain initial informed consent and any re-consent that requires a full revised consent form. 
 
3.4 
IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
 
3.5 
IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval date.   
 


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3.6 
Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course 
of a study, the study participant must sign an authorization statement.  This authorization 
statement may or may not be separate from the informed consent document.  The 
Coordinating Center, with the approval from the DFCI IRB and if applicable NCI/CTEP, 
will provide a consent template, with information regarding authorization for the disclosure 
of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health information 
must be collected. DF/HCC has chosen to use authorizations, signed by the participant in 
the trial, rather than limited data sets with data use agreements. 
 
3.6.1   DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. 
Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating 
Center should be de-identified. It is recommended that the assigned DF/HCC QACT case 
number (as described below) be used for all participant specific documents. Participant 
initials may be included or retained for cross verification of identification.  
 
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
 
All participants must be registered with DF/HCC prior to conducting any research-related 
procedures 
 
3.7.1   Participant Registration and Randomization  
 
Please refer to protocol Section 4.0: Registration Procedures 
 
3.7.2   Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific 
interventions may not be initiated until the Participating Institution receives confirmation 
of the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
 


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3.7.3   Eligibility Exceptions 
 
CTEP specifically prohibits registration of a participant on any NCI Sponsored protocol 
that does not fully and completely meet all eligibility requirements. No exceptions to the 
eligibility requirements for a protocol without DFCI IRB approval will be permitted. All 
Participating Institutions are required to fully comply with this requirement. The process 
for requesting an eligibility exception is defined below. 
 
3.8 
DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 
participant successfully registered, the participant is assigned a unique protocol case 
number.  Participating Institutions should submit all de-identified subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.     
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
  
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
  
 
Protocol Violation: Any protocol departure that was not prospectively approved by the 
IRB prior to its initiation or implementation.   
 
3.8.3  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, 


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deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring 
that all protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the 
DFCI IRB. The Participating Institution must submit the deviation request to the 
Coordinating Center who will then submit the deviation request to the DFCI IRB. Upon 
DFCI IRB approval the deviation is submitted to the Participating Institution IRB, per 
institutional policy. A copy of the Participating Institution’s IRB report and 
determination will be forwarded to the Coordinating Center within 10 business days after 
the original submission. The deviation may not be implemented without all required 
approvals 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the Coordinating Center will submit the report to the DF/HCC 
Sponsor for review. Subsequently, the Participating Institution’s IRB violation/deviation 
report will be submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. 
DF/HCC will forward all violation reports to CTEP via an internal DF/HCC process, as 
applicable. 
 
3.9 
Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated therapy 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center. Protocols using CTEP supplied agents must report these toxicities via the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). The 
DF/HCC Sponsor will be notified of these events via CTEP-AERS. 
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol Section 7: Adverse Events. 
 
 
  
 


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Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND 
Safety Reports are distributed to the Participating Institutions. Participating Institutions 
will review /submit to their IRB according to their institutional policies and procedures. 
  
 
3.10 
Data Management 
 
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  These 
forms are designed to collect data for each study. DF/HCC CTRIO provides a web based 
training for all eCRF users. 
   
3.10.1    Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC Office of Data Quality, 
Coordinating Center, or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report 
form, or in the case of electronic queries, within the electronic data capture (eDC) system. 
In the case of a written query for data submitted on a paper case report form, the query 
must be attached to the specific data being re-submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will 
periodically receive a Missing Form Report from the Coordinating Center noting the 
missing forms.  
 
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of investigational agent is specified in the protocol Section 8: Pharmaceutical 
Information.  
 


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Participating Institutions should order their own agent regardless of the supplier. (i.e., NCI 
or a pharmaceutical company.)   
 
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure 
that the agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed of 
who will supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory 
responsibilities can be met in a timely fashion.  
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data 
Quality, provides quality control oversight for the protocol. 
 
5.1 
Ongoing Monitoring of Protocol Compliance 
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring practices may include but are not limited to 
source data verification, and review and analysis of eligibility requirements, informed 
consent procedures, adverse events and all associated documentation, review of study drug 
administration/treatment, regulatory files, protocol departures reporting, pharmacy records, 
response assessments, and data management.  
 
Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for eligibility confirmation as well as for ongoing, remote monitoring. 
Participating Institution are also be subject to on-site monitoring conducted by the 
Coordinating Center.  
 
Participating Institutions will undergo on-site monitoring by the Coordinating Center within 
3 months of enrollment of the first patient; Combination on-site and remote monitoring will 
occur every 4-6 months thereafter while patients are on treatment or in active follow-up.  
Remote monitoring may be done in lieu of on-site monitoring if no active patients are on 
trial at that site.  Once all site participants are off treatment and in long-term follow-up, 
remote monitoring will be conducted annually for confirmation of long term follow-up data 
and regulatory compliance.   
 
For remote monitoring visits, Participating Institutions will be asked to provide remote 
electronic medical record access to the monitor or will be required to forward redacted 
copies of participants’ medical record and source documents to the Coordinating Center to 
aid in source data verification.  The participants and CRFs to be reviewed at the visit will 
be communicated at least 2 weeks in advance of the scheduled monitoring visit.  Source 
documentation can be provided to the Coordinating Center via an encrypted memory stick 


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or via a secure file transfer system.  During remote monitoring visits, the Site Specific File 
will be reviewed in lieu of the site regulatory binder. 
 
On-Site Monitoring will be scheduled several weeks in advance and will be conducted over 
a 2-3 day period.  During an on-site monitoring visit, 2-4 participants will be monitored as 
well as the complete regulatory binder. Source documentation verification (SDV) will be 
conducted by having access to participants’ complete medical record and source documents.  
Participating Institutions will be expected to coordinate the necessary resources for the 
monitor, including a desk, access to all participant medical and research records (electronic 
and hard copy), the regulatory binders and access to a photocopier.  The Participating 
Institution will also be asked to assist in scheduling a pharmacy visit and a brief exit 
interview on the final day of the visit with the Study Coordinator and the Site investigator. 
 
All Participating Institutions will be required to participate in monthly Coordinating Center 
initiated teleconferences.  Once all participants have completed treatment, teleconferences 
will be scheduled as needed. 
 
5.2 
Monitoring Reports 
 
Following each monitoring visit, a monitoring follow-up report will be provided to the 
Participating Site (i.e. Site PI and Coordinator).  The monitoring report will summarize any 
issued queries or data clarification requests, identify any reportable events or required 
follow-up on prior events and will specify details of any non-compliance.  Participating 
Sites are requested to respond to all queries and data clarifications requests within 10 
business days. 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at Participating Institutions 
that are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and 
local regulations. 
 
5.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. 
 
The minimum accrual per participating site is 3-5 patients annually in consideration of the 
regulatory and monitoring cost and effort of overseeing each site.  
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated 
activities were appropriately conducted and whether data was generated, recorded and 


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analyzed, and accurately reported per the protocol, applicable Standard Operating 
Procedures (SOPs), and the Code of Federal Regulations (CFR). 
 
6.1 
Audit Plan: NCI Sponsored Trials 
 
N/A 
 
6.2 
DF/HCC Internal Audits 
  
 All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality 
(ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2 day 
period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited.  
 
6.3 
Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve this 
protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after the 
audit date.  
 
6.4 
Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.5 
Participating Institution Performance 
 
The DF/HCC Sponsor, DFCI IRB and the NCI for CTEP trials, is charged with considering 
the totality of an institution’s performance in considering institutional participation in the 
protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. A 
DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above.