Conditions: Recurrent Chronic Lymphocytic Leukemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of lenalidomide when given together with R-(-)-gossypol acetic acid and to see how well they work in treating patients with B-cell chronic lymphocytic leukemia (B-CLL) that has returned after a period of improvement (relapsed). Biological therapies, such as lenalidomide, may stimulate the immune system to attack cancer cells. R-(-)-gossypol acetic acid may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and causing the cells to die. Giving lenalidomide with R-(-)-gossypol acetic acid may be an effective treatment for relapsed or refractory B-CLL. - Funding Source - FDA OOPD

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of lenalidomide in combination with AT-101 (R-(-)-gossypol acetic acid). (Phase I) II. To assess the overall response rate of lenalidomide in combination with AT-101. (Phase II)

SECONDARY OBJECTIVES:

I. To assess the overall response rates of lenalidomide in combination with AT-101 at 6 months and 12 months.

II. To evaluate time to progression (TTP) for the combination of lenalidomide + AT-101.

III. To evaluate the safety of this combination in patients with relapsed B-CLL.

TERTIARY OBJECTIVES:

I. To conduct correlative studies for further understanding of the mechanism of antitumor activity of lenalidomide and lenalidomide + AT-101.

OUTLINE: This is a phase I dose-escalation study of lenalidomide followed by a phase II study.

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Beginning in course 3, patients also receive AT-101 PO twice daily (BID) on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months for up to 2 years.

Arms:
arm 1: Patients receive lenalidomide PO QD on days 1-21. Beginning in course 2, patients also receive AT-101 PO BID on days 1-3. Treatment repeats every 28 days for up to 11 courses (49-56 days for course 12 or last course of treatment) in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Lenalidomide intervention 2: R-(-)-Gossypol Acetic Acid intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 


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Protocol Version Date: November 25, 2014 
 
 
Index 
Schema 
  1.0 
Background  
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factor  
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Consent Form  
Appendix I 
ECOG Performance Status Scale 
Appendix II 
Rai Staging System for CLL 
Appendix III 
Criteria for Diagnosis of Disease 
Appendix IV 
Definition of Symptomatic B-Cell 
Appendix V 
Grading Scale for Hematologic Toxicity in CLL Studies 
Appendix VI 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control 
Methods 
Appendix VII Education and Counseling Checklist 
Appendix VIII Lenalidomide Information Sheet 
Appendix IX 
Medication Diary 
 
 


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Protocol Version Date: November 25, 2014 
 Schema 
 
Phase I only: Prior to discussing protocol entry with the patient, call the MCCC Registration Office 
(
) for dose level and to insure that a place on the protocol is open to the patient.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Cycle length = 28 days Cycles 1-11;  Cycle length = 49-56 days Cycle 12 (or last cycle of treatment if patient 
discontinues treatment before Cycle 12) 
 
 
Generic name: AT-101 
Brand name(s): 
Mayo Abbreviation: AT-101 
  
Availability:    
Generic name: Lenalidomide 
Brand name(s): Revlimid 
Mayo Abbreviation: CC5013  
Availability:    
Registration 
Cycle* 1: 
Lenalidomide days 1-21 
 
Cycles* 2-12: 
Lenalidomide days 1-21 
AT-101 days 1-3 
PD at any time 
Unacceptable adverse  
 
Event 
    events   
 
 
Monitoring 
Patient refusal  
 
Observation 
Event Monitoring 


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Protocol Version Date: November 25, 2014 
1.0 
Background   
 
Overview 
CLL is a lymphoproliferative malignant disorder that remains incurable in majority of the patients 
using standard therapeutic approaches.  It is manifested by progressive accumulation of 
functionally incompetent, mature looking lymphocytes in the blood, bone marrow and lymphoid 
tissues.  It is a heterogeneous disease with a variable clinical spectrum ranging from an indolent 
variety (Rai Stage 0) where the patients enjoy a long-term survival of over 12 years vs. advance 
stage disease (Stage III/IV) where the median survival is about 2.5 years 1.  Treatment options 
have included alkylating agents (Chlorambucil, Cyclophosphamide) or purine analogues 
(fludarabine, Pentostatin) and/or monoclonal antibodies (rituximab, alemtuzumab, ofatumumab).  
These agents are often used in combination regimens with variable responses. Treatment of this 
disease remain palliative as the clinical course is punctuated with frequent relapses and eventual 
death of the patient from progressive disease. New agents are thus needed for the treatment of 
relapsed and refractory CLL with curative aim 2.  In reviewing the natural history of this disease it 
is clear that this aim is unlikely until complete remission can be achieved in higher proportions of 
this patient population 3.  
  
Treatment 
Due to the incurable nature of the disease and limited therapeutic options, treatment of CLL is 
often only instituted when patients develop symptomatic or persistently progressive disease. 
Criterion to consider treatment intervention is outlined in the IWCLL/Hallek, December 2008 
formulation (see Appendix IV).  
 
Chemotherapy in CLL  
Initial treatment for CLL patients that require therapy4 include either (a) single agent alkylating 
agent (chlorambucil) or a (b) purine analogue (fludarabine or pentostatin). Compared to 
chlorambucil, higher overall response rate (ORR) and complete responses are observed with 
fludarabine though no superiority in overall or progression free survival was noted in randomized 
studies.5,6 Thus, up until very recently, the standard of care for this disease remained the use of 
single agent oral Chlorambucil or Fludarabine with complete remission (CR) rate of 4% and 20% 
respectively. Kanti Rai reported on the CALGB randomized Chlorambucil vs. Fludarabine vs. the 
combination of Fludarabine and Chlorambucil 6. Among the 170 patients treated with fludarabine 
20% achieved a CR while 43% with a partial remission (PR). The median duration of remission 
and the median progression free survival in this group was 25 and 20 months respectively. 
Despite improvement in the ORR no survival benefit was reported.  
 
Combination of these agents with steroids, and or other chemotherapy agents (such as vincristine 
or an anthracycline) also did not result in improved survival. 7-9 Importantly, even early disease 
stage patients treated with these agents did not alter the overall clinical outcome. Despite 
evaluation of various combination regimens purine analogues are the most active agents in 
patients with CLL, yielding higher overall and complete response rates. 6,10,11 Eventually all 
patients with CLL will relapse. Although retreatment with fludarabine can result in disease, 
especially in those with an initial clinical response lasting for more than 1 year, continued 
treatment with fludarabine is difficult due to cumulative marrow toxicity resulting in prolong 
cytopenia and inability to further treat the patient. Patients who do not achieve durable remission 
after first fludarabine therapy have only a modest response with a second round of fludarabine 12. 
For these patients combination with alkylating agents (cyclophosphamide) has been used with 
improved outcome 10,13,14. Various investigators reported combination of fludarabine with 
cyclophosphamide as salvage regimen in patients with CLL.14,15.  


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Monoclonal antibodies and chemoimmunotherapy  
Rituximab is a chimeric humanized monoclonal antibody that showed an ORR of approximately 
50-60% in patients with relapsed and refractory low-grade non-Hodgkin’s lymphoma 16-18. Since 
CLL is a B-cell lymphoproliferative disease with expression of CD20, rituximab was investigated 
for the treatment of CLL. Interestingly, despite expression of CD-20 on the CLL cells, single 
agent rituximab (on standard dosing schedule) failed to demonstrate any meaningful clinical 
response. Though more frequent dosing i.e., thrice weekly for 4 weeks (at 375mg/m2 per dose) 
showed  a better response rate 45% (3% CR, 42% PR) with a median duration of response of 10 
months 19. Higher doses may have more anti-tumor efficacy but are cost prohibitive, and the true 
long-term benefit remains undetermined. 20 
 
While results of single agent rituximab in CLL were disappointing, combination with fludarabine 
(chemoimmunotherapy) were impressive.21,22 Clinical experience of combination of rituximab 
with fludarabine, or fludarabine and cyclophosphamide demonstrated higher rates of complete 
remission 14,19,20,23-27.  Overall response rates of fludarabine + rituximab combination are in the 
range of 90% with 47% CR 24,28. This strategy of chemoimmunotherapy though yield higher 
response rates, is often associated with significant toxicity and morbidity to the patients.  Despite 
the higher response rates and increase rates of reported CR, all patients eventually relapse and die 
of progressive disease or its complications.  Nevertheless, the chemoimmunotherapy approach is 
now the most commonly used front-line treatment approach in CLL.  Despite these high overall 
and complete response rates all patients eventually relapse and develop resistance to therapy. For 
these patients the only approved therapy is alemtuzumab. 
 
Alemtuzumab  
It is a humanized monoclonal antibody that targets CD52 and demonstrated clinical response in 
over 30% of CLL patients with relapsed or refractory disease.  Again, the CR rate remains low 
(<5%). Several clinical trials are investigating combination of alemtuzumab with chemotherapy 
to improve upon the number of patients achieving a CR. An important and limiting side of 
alemtuzumab has been severe immunodeficiency resulting from depletion of both T and NK cells 
along with B cells. This often results in infectious complications and has limited its use in the 
community.   
 
Immunomodulating agents in CLL 
Cytokines which have been shown in vitro to function as survival factors for CLL lymphocytes 
include: interleukin-2 (IL-2), IL-4, IL-6, IL-8, IL-13, basic fibroblast growth factor (bFGF), 
tumor necrosis factor-alpha (TNF-α), interferon-alpha (IFN-α), and IFN-α 29,30.  Increased 
intracellular and plasma levels of bFGF have been demonstrated in patients with CLL and have 
been correlated with stage of disease. 31,32  CLL lymphocytes with high levels of bFGF are more 
resistant to fludarabine, and exogenously added bFGF impairs fludarabine induced apoptosis, 
possible through the induction of the anti-apoptotic protein bcl-2. 30,33 
 
Immunomodulating agents (thalidomide and lenalidomide) are a new class of anti-cancer agents 
with antitumor activity in multiple myeloma and myelodysplastic syndrome. The exact 
mechanism of action of thalidomide remains unclear though investigators have reported its effects 
on down regulation of IL-6, IFN-α, VEGF and bFGF. It has been reported to alter the bone 
marrow microenvironment of patients with multiple myeloma by changing the cytokine milieu 
thus rendering the environment unfavorable for tumor growth and progression. 
 


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Protocol Version Date: November 25, 2014 
We investigated thalidomide in combination with fludarabine for treatment of patients with newly 
diagnosed CLL.  The phase I part of this study did not demonstrate and dose limiting toxicity of 
thalidomide (up to 300mg daily dose) when combined with standard dose fludarabine. The Phase 
II part of the study to date had 30 patients enrolled. Preliminary results of this study were reported 
and demonstrate overall response rate of 100% (vs. 43% with fludarabine alone – historical 
control). The complete response rate is over 70% (vs. 23% with fludarabine alone – historical 
control). An interesting observation was a sudden decrease in absolute lymphocyte counts in 
peripheral blood with single agent thalidomide prior to instituting fludarabine. These findings 
encouraged us to investigate lenalidomide, a more potent derivative of thalidomide. Like 
thalidomide, lenalidomide too is reported to stimulate T-cells proliferation and activation. It is 
noted to be 50-2000 times more potent than thalidomide in stimulating T-cell proliferation and 
about 50-100 times more effective in increasing the production of IL-2 and INF-γ. It is also noted 
to decrease the production of IL-6, TNF-α, VEGF, bFGF and IL-1β.  Recently, lenalidomide was 
approved for the treatment of patients with multiple myeloma (another B-cell malignancy) as well 
as myelodysplastic syndrome with deletion 5q.  
 
Lenalidomide in CLL 
We hypothesized that lenalidomide with its ability to modulate the cytokine milieu and its 
immune stimulatory properties will be able to modulate the CLL cell microenvironment and thus 
compromise CLL survival. Preclinically our group had also observed that lenalidomide augments 
anti-lymphoma activity of rituximab in mouse xenograft model.   Thus we initiated a phase II 
study investigating the antitumor activity of lenalidomide alone in patients with relapsed or 
refractory B-CLL. Those patients who would develop disease progression on lenalidomide alone 
will then have rituximab added to lenalidomide for additional 6 cycles of treatment.   
 
In the first report of lenalidomide single agent in CLL we observed that over 47% of the patients 
who receive single agent lenalidomide demonstrated a clinical response and among these 7% 
achieved a complete remission as per the 1996 NCI-WG Cheson criteria (median follow-up of 1 
year). Additionally, 4 of the 5 patients who achieved a complete response actually were noted to 
have a molecular response in the peripheral blood and bone marrow.    
 
A unique side effect of lenalidomide that was also observed with thalidomide was the tumor flare 
reaction.  Clinically this presented with sudden onset tender enlargement of the disease involved 
lymph nodes, spleen or liver.  This was often associated with low-grade fever, rash and in some 
cases actually an increase in the absolute lymphocyte counts. Some people also complained of 
pain in bones.  Typically this was a first cycle phenomenon with a median duration of 14 days 
(range 1-21 days) and was suggestive of an immune activation syndrome. Interestingly, severity 
of the tumor flare tends to correlate with the quality of clinical responses observed.      
 
Correlative studies conducted revealed several interestingly findings: First we observed that in 
vitro lenalidomide have no direct proapoptotic activity on B-CLL cells, secondly we observed 
that patients who had normal or high baseline levels of NK-cells tend to have a better quality 
clinical responses and that this correlated with the severity of tumor flare reaction, thirdly we 
observed upregulation of costimulatory molecules (CD80, CD86 and CD40) on B-CLL cells 
upon treatment with lenalidomide in vitro or in vivo (samples obtained from patients before and 
after treatment with lenalidomide) and lastly we observed that lenalidomide down regulated p-
Akt and p-Erk1/2 but not Bcl-2 or Bcl-xl in B-CLL cells in vitro or in vivo (samples obtained 
from patients before and after treatment with lenalidomide).  
 


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Protocol Version Date: November 25, 2014 
While the clinical responses observed with single agent lenalidomide are encouraging in the 
relapsed and refractory population treated, most patients remained in partial remission and only a 
limited number of patients were able to achieve complete remission. Thus lenalidomide based 
therapeutic approach needs to be further optimized possibly using combination with other 
therapeutic agents.  To this effect our correlative studies are instrumental in defining rationale 
combination for further investigations.  
 
Bcl-2 is an important therapeutic target in B-CLL  
The antiapoptotic protein Bcl-2 is over-expressed in all cases of CLL and enhances the leukemia-
cell survival and resistance to cell-death caused by anti-cancer drugs or immune therapy.  This 
makes Bcl-2 is an attractive therapeutic target in CLL.  CLL has been classically understood as a 
disease more of impaired apoptosis than excessive proliferation.  B-CLL cells have numerous 
defects in the normal apoptotic pathways.  Prominent among these are abnormalities involving 
members of the Bcl-2 family.  This family includes proteins, such as Bcl-2, Bcl-xL, Bcl-w, Mcl-
1, and A1, which inhibit apoptosis; and other proteins, such as Bax, Bak, and others.  Inhibition 
of apoptosis by Bcl-2 appears principally due to its ability to bind the shared BH3 domain of 
proapoptotic members, thereby inactivating the latter.  Disruption of this binding, in turn, 
increases a cell’s susceptibility to undergo apoptosis.34   Overexpression of the anti-apoptotic 
protein Bcl-2 has been observed in CLL B cells,35-37 as has an increased ratio of Bcl-2 to the 
related proapoptotic protein, Bax.  Increased Bcl-2 expression and an increased Bcl-2/Bax ratio 
have further been reported to be associated with resistance of CLL B cells to chemotherapeutic 
agents in vitro and with poor clinical prognosis.38-41 Also, apoptosis of CLL-B cells has been 
reported to be associated with conformational changes of Bax and Bak.42,43 Presence of a 
common polymorphism in the promoter region of the bax gene has been reported to be associated 
with lower Bax protein levels, higher Bcl-2/Bax and Mcl-1/Bax ratios, and shortened patient 
survival in CLL.44 In a recently reported prospective clinical trial of standard first-line therapy of 
patients with CLL, two factors—elevated expression of Bcl-2 protein or presence of a p53 
abnormality (either as a result of p53 mutation or del 17p)—were associated with a reduced 
likelihood of complete response to treatment45.  The negative association between these two 
factors and treatment response was stronger than for other important prognostic factors in CLL, 
including the expression of another antiapoptotic member of the Bcl-2 family, Mcl-1.  A small 
molecule BH3 mimetic, designed to inhibit the binding of Bcl-2 to proapoptotic family members, 
increased the susceptibility of CLL B cells to apoptosis,45 as did treatment with an antisense 
oligonucleotide against 
Bcl-2,46 
while 
an 
antisense 
oligonucleotide against 
Bax 
reduced 
the 
susceptibility of CLL B 
cells 
to 
apoptosis.47   
Adding 
a 
Bcl-2 
antisense 
oligonucleotide 
to 
standard 
therapy 
of 
patients 
with 
CLL 
increased 
their 
likelihood of achieving 
a complete response or 
nodular 
partial 
response 
in 
a 


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Protocol Version Date: November 25, 2014 
prospective, randomized trial, although the trial design did not permit an assessment of the effects 
of treatment on Bcl-2 function.48   Mcl-1 expression has also been associated with reduced 
response of CLL to therapy.49-51   
 
Combining lenalidomide with Bcl-2 targeting drug 
Since our correlative studies fail to demonstrate any effect of lenalidomide on Bcl-2 or Bcl-xl, an 
inhibitor of Bcl-2 with an acceptable safety and dosing profile could have a potentially beneficial 
effect when combined with lenalidomide for the treatment of B-CLL patients. To investigate this 
we conducted preclinical studies summarized that are summarized below: 
 
Preclinical evaluation of lenalidomide in combination with AT-101 
AT-101, a pan-Bcl-2 inhibitor, induces apoptosis in CLL: AT-101 is a novel, orally active 
BH3-mimetic that inhibits the activity of Bcl-2-family-
member proteins including Bcl-2, Bcl-xL, and Mcl-1 
inducing death in CLL cells.  We evaluated the effect of 
AT-101 on Bcl-2 expression and cell survival in our 
CLL cell line (MO1043) and primary CLL cells 
obtained from patients and noted a dose dependent 
decrease in Bcl-2 levels (Fig 1).  AT-101 decreased Bcl-
2 expression and cell viability of the MO1043 cell line 
in a dose dependent manner and this effect was 
validated in primary CLL cells from patients. 
 
Bcl-2 downregulation by AT-101 enhance immune 
killing mediated by lenalidomide:  We then 
investigated if Bcl-2 downregulation with AT-101 can 
help enhance immune cell directed killing.  We treated 
normal human PBMC (containing immune effector 
cells) with lenalidomide (1 µM for 48 h) and used them 
as effector cells to kill the MO1043 target cells that 
were pretreated with AT-101 (2.5 µM AT-101 for 4 h) 
in ADCC assay with 50:1 ratio for 4 h.  We noted a 
significantly increased lysis of target leukemic cells 
when 
the 
effector 
cells 
were 
pretreated 
with 
lenalidomide 
(Fig 
2). 
 
This 
suggests 
that 
downregulation of Bcl-2 with AT-101 can enhance 
susceptibility of leukemic cells to immune mediated 
killing 
and 
affirms 
the 
rationale 
to 
combine 
lenalidomide (an immune stimulatory agent) with AT-
101 a Bcl-2 targeting agent for the treatment of CLL.  
 
 
 
Lenalidomide can also enhance anti-CLL effects of 
AT-101: lenalidomide is not directly cytotoxic to CLL 
cells, however it can modulate the phenotype of the 
leukemic blasts.  It is thus possible that lenalidomide 
may engage other mechanism(s) (independent of 
immune effector cells) that can cooperate with AT-101 
and enhance CLL cell killing.  To evaluate if 
lenalidomide treatment sensitizes CLL cells to AT-101 


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Protocol Version Date: November 25, 2014 
induced death in an immune independent manner, MO1043 CLL cell line was treated with 
increasing concentration of AT-101, lenalidomide and combination of both.  As anticipated, in 
the absence of immune cells, lenalidomide did not have any significant effect on the viability of 
leukemic cells (determined by the trypan blue assay) while AT-101 demonstrated a dose 
dependant decrease in cell viability.  Interestingly, pretreatment of leukemic cells with 
lenalidomide significantly enhanced the anti-CLL effects of AT-101 (Fig 3).  This may suggest 
lenalidomide’s effect on other prosurvival pathway(s) such as the Akt, Erk1/2, which 
independently may not be sufficient to kill CLL cells but in conjunction with downregulation of 
another survival pathways (Bcl-2) may compromise survival. 
 
Summary of preliminary data and rationale for clinical trial proposal:  We have found that 
lenalidomide is clinically active in patients with CLL.  The anti-leukemic effect of lenalidomide 
is mediated through activation of a robust immune response that is dependent upon NK and T 
cells and clinically manifests as a flare reaction.  The intensity of this immune reaction correlates 
with pretreatment levels of immune effector cells and with the depth of response.  The maximal 
clinical benefit that can be harnessed with lenalidomide is truncated by the compromised 
immunity (dysfunctional T and NK cells), known to exist in CLL patients.  An important 
component in undermining the efficacy of the anti-leukemic immune response is the inherent 
molecular makeup of the CLL cell and the presence of the antiapoptotic Bcl-2 protein.  Since 
lenalidomide does not have any effect in decreasing Bcl-2 levels in CLL cells, we hypothesized 
that therapeutic downregulation of the antiapoptotic protein Bcl-2, may help maximize the killing 
potential of immune effector cells that are activated by lenalidomide.  AT-101, an orally available 
BH-3 mimetic, was investigated and demonstrated effective downregulation of Bcl-2.  The anti-
leukemic effect of AT-101 in primary CLL cells revealed that AT-101 was particularly more 
effective in cell that had higher basal Bcl-2 protein levels.  Furthermore, downregulation of Bcl-2 
in CLL cells in vitro enhanced the killing potential of lenalidomide activated immune cells.  
Conversely, pretreatment of CLL cells with lenalidomide enhanced the cytotoxicity of AT101 in 
an immune cell independent manner.  Thus our preliminary findings support the role of a Bcl-2 
targeting agent(s) in augmenting clinical efficacy of immune directed therapies such as 
lenalidomide.  The proposed clinical trial will therefore investigate the feasibility of a novel 
combination of an orally available Bcl-2 (AT-101) in combination with oral lenalidomide as a 
potential path for strategic development of AT-101. 
 
Racemic Gossypol 
Racemic gossypol has been consumed as a constituent of the human diet (primarily in cottonseed 
meal and oil) or as a component of folk medicines (e.g. for the treatment of chronic bronchitis 
and cough) for many years.  After studies demonstrated that gossypol purified from cotton seeds 
had antispermatogenic effects in animals, racemic gossypol was evaluated in clinical trials as a 
potential male anti-fertility agent.52  Studies in over 9,000 men, conducted primarily in China, 
demonstrated that oral racemic gossypol (7.5 to 20 mg/day) was an effective male contraceptive 
and was generally well tolerated.  Adverse effects included fatigue, gastrointestinal symptoms, 
mild hypokalemia and an irreversible contraceptive effect in some patients.  Hypokalemia was 
rare in studies conducted outside China.53  Ovarian suppression and endometrial atrophy by 
racemic gossypol has also been described; racemic gossypol is approved by the Chinese State 
Food and Drug Administration as a treatment for endometriosis, dysfunctional bleeding of the 
uterus, and uterine myoma. 
 
In the 1980’s and 1990’s, nonclinical studies determined that racemic gossypol had cytotoxic 
effects in human breast, prostate, colon, melanoma, and adrenal carcinoma cell lines.  


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Consequently, the safety and antitumor activity of single-agent, oral racemic gossypol acetic acid 
were evaluated in over 100 patients with advanced cancers (metastatic adrenal cancer, recurrent 
adult malignant glioma, metastatic breast cancer, advanced solid tumors) in four clinical trials 
conducted in the  U.S. and U.K.  Patients received oral doses of racemic gossypol acetic acid 
ranging from 30 to 180 mg weekly or 20 to 70 mg daily (primarily in divided doses), until disease 
progression or toxicity. 54-57 
 
Tumor responses and stable disease were also reported in these early-stage, uncontrolled studies 
in a variety of cancers.  Partial responses were observed in 2/15 patients with relapsed/refractory 
glioblastoma multiforme, and 3/21 patients with metastatic, previously treated adrenal carcinoma.  
These responses were associated with improvement in clinical symptoms and, in two cases (1 
glioblastoma, 1 adrenal) were reported to have a duration of a year or more with continued 
therapy. 
 
Reported side effects of repeat treatment were mild or moderate and included gastrointestinal 
adverse events (nausea, vomiting, diarrhea, transient ileus, anorexia), transaminitis, fatigue, 
peripheral edema, and rash.  Hypokalemia and hematologic toxicity were rare.  Most patients 
discontinued gossypol treatment due to disease progression and not due to toxicity.  The MTD for 
racemic gossypol was estimated in three of the studies, and ranged from 30 mg/day to 50 or 60 
mg/day for daily treatment, and 120 mg/week for weekly treatment.  The best estimate of the 
MTD for daily administration of racemic gossypol was 40 mg/day. 56   
 
Non-clinical in vitro and in vivo studies have demonstrated that the antitumor activity of racemic 
gossypol appears to reside principally in the R-(-)-enantiomer, with reduced activity observed for 
the S-(+)-enantiomer.  Consequently, Ascenta Therapeutics, Inc. is evaluating R-(-)-gossypol 
acetic acid (AT-101) as a treatment for advanced cancer. 
 
AT-101  
 
AT-101 is levorotatory enantiomer of gossypol acetic acid, R-(-)-gossypol acetic acid; the 
chemical name is R-(-)-1,1’, 6,6’,7,7’-hexahydroxy-3,3’-dimethyl-5,5’-bis (1-methylethyl) [2,2’-
Binapthalene]-8, 8’-dicarboxaldehyde acetic acid (figure 1). AT-101, administered orally is a 
BH3-mimetic inhibitor of Bcl-2 family-member-proteins (Bcl-2, Bcl-xl, Mcl-1, Bcl-w) that 
induces apoptosis in CLL cells. The oral formulation makes this compound more attractive to 
combine with other oral compounds such as oral lenalidomide. Recently Castro et al reported the 
preliminary results of an ongoing phase II clinical trial of oral AT-101 in combination with 
rituximab among patients with relapsed or refractory B-CLL. In the preliminary report presented 
at the 2006 annual meeting of the American society of hematology (ASH), 12 patients have 
received AT-101, at 30mg/d, for 21 or 28 days during each of three 28-day cycles. Rituximab was 
administered at 375 mg/m2 for 12 doses (total dose = 4,500 mg/m2) on days 1, 3, 5, 8, 15, 22, 29, 
31, 33, 57 59, 61. The patients’ median age was 62 years (range 43-82). Six patients were high 
risk and five were intermediate risk based on the modified Rai classification. The median number 
of previous treatments was 2.5 (range 1-11). Eight patients interrupted treatment due to adverse 
events, most of which were transient and without residual complications. Gastrointestinal and 
constitutional effects were the most common adverse events. Two patients had Grade II ileus 
(small bowel obstruction). Six patients experienced treatment-associated fatigue (grade I-II in five 
patients and grade III in one patient). The only grade III/IV event believed related to AT-101 was 
fatigue. One patient died while undergoing treatment from community-acquired bacterial 
pneumonia; the patient developed grade IV neutropenia, septic shock, and renal failure during the 
course of the infection. These events were considered unrelated to AT-101. The combination of 


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AT-101 and rituximab appears active in relapsed/refractory CLL. Correlative studies presented 
demonstrated down regulation of Bcl-2 and Mcl-1 in tumor cells obtained from patients.  
 
In a second report presented at the 2007 annual meeting of ASH, Castro et al presented initial 
results from a second cohort (n=6) treated with intermittent, pulse AT-101, 80 mg/d on days 1-3 
and 15-17 of each 28-day cycle, in combination with weekly rituximab, 375 mg/m2/week. Six (6) 
patients have received pulse AT-101. Patient demographic characteristics and risk prognostic 
status (ZAP70, IgVH mutational status, and cytogenetics / FISH) are comparable between the two 
dose cohorts. Gastrointestinal (GI) toxicity, the most notable adverse effect of AT-101 with daily 
administration, appears reduced with intermittent AT-101; 2/6 patients have had NCI-CTCAE 
Grade 1-2 GI toxicity, and 0/6 have had Grade 3-4 ileus, compared with 11/12 and 2/12 patients, 
respectively, in the daily dose cohort. Apoptosis of CLL cells evaluated by Annexin V FACS at 
the time of maximum AT-101 concentration, was present in 18-45% of cells in 4 of the 6 patients 
after a single 80 mg dose of AT-101. By comparison, apoptosis after a 30 mg AT-101 dose 
appeared lower and was detected in approximately 1-15% of cells. After 80 mg of AT-101, 
plasma concentrations of up to 6.6 M have been observed compared with concentrations of 
approximately 0.8-1.8 M after a 30 mg dose in the daily dose cohort. In the pulse AT-101 cohort 
we have observed partial responses (PR) in 3 patients while the other 3 are still receiving 
treatment. Five (5) out of 12 patients had a PR in the previously reported AT-101 continuous 
administration group. 
 
Intermittent administration of AT-101 with a pulse dose regimen appears associated with an 
increased pro-apoptotic effect in vivo and higher plasma concentrations, as well as reduced 
toxicity, when compared with daily dosing. 
 
Chemical Structure of R-(-)-Gossypol 
 
As summarized below racemic gossypol and R-(-)-gossypol (AT-101) bind to and inactivate anti-
apoptotic members of the Bcl-2 gene family that are elevated in a variety of cancers.   
 
Non-Clinical Pharmacology  
The Bcl-2 family of proteins plays an essential role in regulating apoptosis, or programmed cell 
death.  Over-expression of two anti-apoptotic members of this family, Bcl-XL and/or Bcl-2, is 
frequently found in a wide variety of human cancers and may contribute to chemotherapy 
resistance.  The experimental structures of Bcl-XL and Bcl-2 showed that BH1 (Bcl-2 homology 
domain 1), BH2, and BH3 domains form a hydrophobic BH3 binding pocket into which the 
endogenous inhibitors of Bcl-2 and Bcl-XL, bind.  Through structure-based computational 
screening, Ascenta discovered that gossypol is a potent, small-molecule inhibitor targeting the 
BH3 domain of Bcl-2/Bcl-XL proteins. 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
Studies by Ascenta and its collaborators have demonstrated that: 
• 
Both gossypol enantiomers bind to the anti-apoptotic proteins Bcl-XL and Bcl-2 in vitro with 
similar affinity and block the binding of pro-apoptotic Bcl inhibitor proteins such as Bid and 
Bak.  Nuclear magnetic resonance (NMR) three-dimensional solution structure data confirm 
that both gossypol enantiomers bind to the BH3-binding pocket of Bcl-XL where the BH3 
domain of pro-apoptotic proteins bind. 
• 
R-(-)-gossypol is more potent than S-(+)-gossypol or racemic gossypol at inhibiting 
proliferation and inducing apoptosis in cancer cell lines in vitro.  For example, in the National 
Cancer Institute (NCI) in vitro screen of 60 cell lines from multiple human tumors the 
average 50% growth inhibition (GI50) value for R-(-)-gossypol was 0.57 µM, whereas the 
GI50 value was 2.1 µM for racemic gossypol and 14.5 µM for S-(+)-gossypol.  
R-(-)-Gossypol induced apoptosis in a dose dependent manner in cancer cells that over-
express Bcl-2 or Bcl-XL, but has little effect on normal cells with low Bcl-XL and Bcl-2 
expression.  The ability of R-(-)-gossypol to induce apoptosis in cancer cells is correlated 
with the level of Bcl-XL; apoptosis is induced via caspase activation.  R-(-)-gossypol’s anti-
proliferative activity is correlated with target cell Bcl-XL/Bcl-XS expression ratios. 
• 
Gossypol inhibits mitochondrial functions regulated by Bcl-2/Bcl-XL. 
• 
R-(-)-gossypol acts synergistically with standard chemotherapeutic agents and radiation in 
inhibiting cancer cell proliferation. 
• 
R (-) gossypol has in vivo tumor growth inhibition activity as a single agent in a variety of 
xenograft models in mice.  The combination of gossypol with docetaxel, cisplatin, CHOP 
(cyclophosphamide, doxorubicin, Oncovin, and prednisone) or radiation achieved 
significantly greater tumor growth inhibition than either treatment alone in xenograft models. 
• 
R (-) gossypol is a potent inducer of the pro-apoptotic proteins Noxa and Puma in numerous 
cancer cell lines, providing an additional mechanism by which AT-101 promotes apoptosis 
• 
Stromal cells protected CLL B-cells from spontaneous and fludarabine-induced apoptosis by 
increasing the Mcl-1 protein levels. However, AT-101 induced similar extent of down-
regulation of Mcl-1 and apoptosis in CLL lymphocytes cultured in suspension or on stroma. 
Stromal cells expressed undetectable levels of anti-apoptotic but high levels of activated ERK 
and AKT proteins and had low or no apoptosis with AT-101. Collectively, these data 
demonstrate 
that 
AT-101 
induces 
apoptosis 
in 
CLL 
B-cells 
and 
overcomes 
microenvironment-mediated resistance while sparing normal stromal cells. 
 
Clinical safety data with AT-101 
 
As of November 2008 approximately 620 patients have been enrolled to 14 Phase 1-2a clinical 
trials of AT-101 as a single agent or in combination with standard agents for the treatment of 
patients with advanced solid tumors, lymphoma, or chronic lymphocytic leukemia. Patients have 
received AT-101 once or twice daily, every day for 21 out of every 28 days or using ‘pulse’ 
schedules administering AT-101 once weekly or b.i.d. for 3 days every 2 or 3 weeks in these 
trials. The phase 2 recommended doses are 20 mg daily for 21 of 28 days or 40 mg b.i.d. x 3 days 
every 21 days.  
 
Clinical trials with AT-101 are ongoing; however, preliminary safety data show that the most 
common AEs, when AT-101 is administered on a once daily schedule, have been gastrointestinal 
(GI) and Grade 1/ 2 fatigue. The GI AEs include nausea, vomiting, abdominal pain, abdominal 
discomfort, diarrhea, constipation, and non-mechanical small bowel obstruction. The most 
common SAEs reported include nausea, vomiting, and ileus, after several months of continuous 
dosing. Reversible elevation of ALT and AST were dose-limiting at doses greater than 40mg/day, 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
when AT-101 was administered daily for 21/28 days, in the initial Phase 1 trial. Non-mechanical 
small bowel obstruction was the dose limiting toxicity at doses ≥ 120mg/day administered once 
weekly or at doses ≥ 40mg BID administered on days 1-3, every other week. Following periodic 
safety reviews, Ascenta has modified the dosing schedule of single-agent AT-101 to include a 
drug ‘holiday’ and has reduced the dose of single-agent AT-101, when administered daily, to 
20mg/day for 21/28 days. Additionally, Ascenta is also investigating shorter periods of exposure 
(pulse dosing) of AT-101 as a single agent and in combination with standard agents. A 
preliminary comparison of SAEs and AEs among patients treated on Phase 2 trials with AT-101 
at 30mg/day and 20mg/day for 21 of 28 days has demonstrated a reduction in the rate of GI SAEs 
and AEs. In addition, as of July 2008, approximately 160 patients have been treated with AT-101, 
in combination with docetaxel or docetaxel/prednisone, given b.i.d. for 3 days every 3 weeks. A 
preliminary review of SAEs and AEs among these patients suggests that AT-101 does not 
augment the cytopenias, GI toxicity, or neuropathy associated with docetaxel administration. As 
of July 2008, only one case of ileus has been reported among approximately 160 patients treated 
with AT-101 40 mg b.i.d. x 3 days every 3 weeks.  As this patient was treated on a blinded trial, 
exposure to AT-101 is not certain. 
 
As of June 2007, there have been 102 SAEs reported after treatment with oral AT-101. Twenty-
nine patients have had events that represent, or may represent, non-mechanical small bowel 
obstruction. Several of these events were considered by the investigator to be unrelated to AT-
101, but nonetheless prompted brief hospitalization and interruption of AT-101 dosing, with 
resolution of symptoms 2-10 days later in most patients. Two patients were successfully re-
challenged at a lower dose. These events tended to occur at higher doses and typically had an 
onset later than 4 weeks after the first dose of AT-101. The dosing regimens associated with these 
events involved continuous daily dosing, dosing for 21 out of 28 days, and pulse schedules. 
Recent modifications in the dose and schedule of AT-101 have suggested a reduction in the 
incidence of severe GI toxicities. For example, as of November 1, 2008, among approximately 
200 patients treated on 3 trials using the combination of AT-101 40 mg b.i.d. x 3 days on days 1-3 
with docetaxel 75 mg/m2 on day 1, repeated every 21 day, there is only one (1) patient who 
developed non-mechanical small bowel obstruction.  Further investigations into other doses and 
schedules of AT-101 are underway.  
 
Phase I studies on the combination of AT-101 with radiotherapy and temozolomide and 
radiotherapy and docetaxel and 5-FU are ongoing in patients with glioblasoma multiforme and 
esophageal cancers, respectively. The phase 2 dose of AT-101 recommended in combination with 
temozolomide and radiotherapy for GBM is 20 mg daily, Monday through Friday, throughout RT 
administration.  A phase I/II study on the combination of AT-101 with topotecan is ongoing in 
patients with relapsed and refractory small cell lung cancer and has enrolled 30 patients. 
 
 
We also conducted in vitro studies of AT-101 and observed its ability to induce apoptosis in B-
CLL cells. Thus, AT-101 is a novel, oral agent with ability to target Bcl-2 family of anti-
apoptotic protein that has demonstrated in vitro and in patient anti-CLL activity. Collectively the 
pre-clinical and clinical data available and presented here and the data available on Lenalidomide 
allow us to put forward the following hypothesis:  


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
Hypothesis: Concurrent targeting of B-CLL 
cell microenvironment by lenalidomide and 
the tumor cell itself by AT-101 will result in 
an enhanced antileukemic effect (Fig 4).  
Therefore we propose to conduct a phase I/II 
clinical trial to first determine the maximum 
tolerated dose of fixed dose of AT-101 in 
combination 
with 
escalating 
doses 
of 
Lenalidomide and subsequently investigate 
the clinical efficacy of this combination.  
 
Rationale for the combination and dosing:  
Developing a novel regimen for relapsed 
/refractory B-CLL patients is an unmet need. 
AT-101 and lenalidomide have been tested in 
phase II studies independently and have 
demonstrated anti-leukemic potential. Despite encouraging results most patients only achieved 
partial remission with single agent use of these agents. There are several important reasons that 
rationalize to develop the combination of lenalidomide with AT-101 these are; (1) both have 
clinically active in patients with B-CLL (2) They have non overlapping toxicities (major toxicity 
for lenalidomide is hematologic while that for AT-101 is gastrointestinal) (3) both an be delivered 
orally and are patient convenient (4) Both have mutually exclusive targets (lenalidomide targets 
the microenvironment and results in immune activation while AT-101 down regulates the 
prosurvival signals of Bcl-2 family of proteins i.e., Bcl-2, Mcl-1 resulting in enhanced 
susceptibility to undergo apoptosis).  
 
We will initiate lenalidomide at 5mg per day, while using the sample 21 out of 28 day cycle 
schedule as published previously.  This is the minimum dose at we were able to demonstrate 
antileukemic effects of lenalidomide. The dose of lenalidomide will be escalated over 4 cohorts 
as outlined later in the study protocol. Although the administered dose in our previous study was 
25mg / day the most tolerable dose (in terms of hematologic) was 20mg / day. Therefore in this 
study we propose that the maximum dose to be investigated in combination with AT-101 be 
20mg/day.  
 
The maximum administered daily dose of AT-101 in a phase II study (in combination with 
rituximab) is 30mg/day for 21 out of 28-day schedule. Although clinical activity was noted at 10 
mg / day dose as well which was considered be also the dose that had the least toxicity.  Using a 
pulse administration schedule, 80 mg/d for 3 days or 40 mg b.i.d. for 3 days every cycle have 
demonstrated augmented apoptosis in CLL and other diseases. Since the premise of this study is 
to constantly render microenvironment unfavorable while at the same time make tumor cell 
vulnerable to death through interruption of the prosurvival signals mediated through Bcl-2 
antiapoptotic protein, a maximal pulse dose of AT-101 that can be intermittently delivered is thus 
favored. In this study therefore, the dose of the AT-101 will remain stable throughout the various 
cohorts.  
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
2.0 
Goals    
 
2.1 
Primary 
 
2.11 
Phase I:  Determine the maximum tolerated dose (MTD) of lenalidomide in 
combination with AT-101. 
 
2.12 
Phase II:  To assess the overall response rate of lenalidomide in combination with 
AT-101.  
 
2.2 
Secondary 
 
2.21 
To assess the overall response rates of lenalidomide in combination with AT-101 
at 6 months and 12 months. 
 
2.22 
To evaluate time to progression (TTP) for the combination of lenalidomide + 
AT-101. 
 
2.23 
To evaluate the safety of this combination in patients with relapsed B-CLL.   
 
2.3 
Correlative Research 
 
2.31 
To conduct correlative studies for further understanding of the mechanism of 
antitumor activity of lenalidomide and lenalidomide + AT-101. 
 
3.0 
Patient Eligibility    
 
Phase I only: Prior to discussing protocol entry with the patient, call the MCCC 
Registration Office (
) for dose level and to insure that a place on the protocol is 
open to the patient.  
 
3.1 
Inclusion Criteria  
 
3.11 
Understand and voluntarily sign an informed consent form. 
 
3.12 
 Age ≥ 18 years. 
 
 
 
3.13 
Able to adhere to the study visit schedule and other protocol requirements. 
 
3.14 
Diagnosis of B-CLL, confirmed by flow cytometric analysis and as per the 
criteria outlined by the IWCLL/Hallek December 2008. (Refer to Appendix  III).  
 
3.15 
Any prior therapy for B-CLL must have been discontinued ≥ 28 days prior to 
registration. 
 
3.16 
Patients must have an absolute lymphocyte count (ALC) of more than 5,000 
cell/mm3.  
 
3.17 
During Phase I:  All patients with relapsed disease will be eligible if they have 
received at least 1 prior standard CLL therapy* and no more than 4 prior 
therapies (one of which must be a purine analog and/or an alkylating agent).  
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
During Phase II:  All patients with relapsed disease will be eligible if they have 
received a minimum of 1 prior standard therapy* and a maximum of 2 prior 
treatments (one of which must be a purine analog and/or an alkylating agent) for 
B-CLL and have developed relapse disease.   
 
 
Note:  Patients who have refractory disease (defined as – progressive disease on 
last treatment, or less than 6 months of clinical response to the last treatment) 
will not be eligible. 
 
 
* Standard Therapies are defined as those listed in the NCCN guidelines for 
treatment of CLL.  
 
3.18 
ECOG performance status of 0, 1 or 2 at registration (see Appendix I). 
 
3.19a 
The following laboratory values obtained ≤ 14 days prior to registration: 
• 
Absolute neutrophil count ≥ 1500/mm3 
• 
Platelet count ≥ 30,000/mm3 
• 
Serum creatinine ≤ 1.5 x ULN. 
• 
Total bilirubin ≤ 1.5 mg/dL or direct bilirubin ≤ 1.0 mg/dL for patients with 
Gilbert’s syndrome 
• 
SGOT (AST) and SGPT (ALT) ≤ 2 x ULN or ≤ 5 x ULN if hepatic disease is 
present. 
 
3.19b Females of childbearing potential (FCBP) † must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL 10 – 14 days prior to and 
again within 24 hours before starting 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.  All patients must be counseled at a minimum of 
every 28 days about pregnancy precautions and risks of fetal exposure.  See 
Appendix VI: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods, AND also Appendix VII: Education and 
Counseling Guidance Document and Appendix VIII:  lenalidomide information.  
 
 
 
† A female of childbearing potential is a sexually mature woman 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). 
 
3.19c   All study participants must be registered into the mandatory RevAssist ® 
program, and be willing and able to comply with the requirements of RevAssist® 
 
3.19d Patients must require treatment for symptomatic B-Cell CLL as defined by the 
IWCLL/Hallek, December 2008 criterion (see Appendix IV) or as determined 
clinically necessary by the treating physician.  
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
3.19e 
Willing to provide blood and baseline bone marrow aspirate samples for 
correlative research purposes (see Sections 6.31 and Section 14.0). 
 
3.2 
Exclusion Criteria  
 
 
3.21 
Any serious medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from signing the informed consent form. 
 
3.22 
Pregnant or lactating females. 
 
3.23 
Any condition, including the presence of laboratory abnormalities, which 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. 
 
3.24 
Use of any other experimental drug or therapy ≤28 days prior to registration. 
 
3.25 
Known hypersensitivity to thalidomide or lenalidomide. 
 
3.26 
The development of erythema nodosum if characterized by a desquamating rash 
while taking thalidomide or similar drugs. 
 
 
3.27  
Patients with history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix, unless in complete remission and off therapy for 
that disease for >3 years).  
 
3.28 
Patient with history of cardiac arrest within the past 6 months. 
 
3.29a Patients with history of prior bowel resection, malabsorption syndrome, 
inflammatory bowel disease, prior bowel obstruction (partial or complete), 
Crohn’s disease, or any other disease significantly effecting the gastrointestinal 
tract. 
 
3.29b Prior use of gossypol or AT-101. 
 
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
4.0 
Test Schedule 
 
 
Active Monitoring Phase 
Tests & Procedures 
Days Prior to 
Registration 
Cycle 1 
Prior to 
subsequent 
Cycles 2-12 
Study Drug 
Discontinuation 
Observation 
 
≤ 28 
days 
≤ 14 
days 
 
 
3-4 weeks from 
the last dose 
Every 3 months 
x 2 years 
Complete medical history 
X 
 
 
 
 
 
Adverse event assessment 
X 
 
X 
X 
X 
Physical exam, including weight and vital signs, and PS1 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Tumor measurement by physical exam2, 3 
X 
 
X 
X 
X 
CT scans (Chest, Abdomen, Pelvis)4 
X 
 
 
 
X 
 
EKG/ECHO5 
X 
 
 
 
 
 
CBC with differential6 
 
X 
X 
X 
X 
X 
Chemistry group (SGOT [AST], SGPT [ALT], serum creatinine,  
total bilirubin18, LDH, uric acid, phosphorus, alk phos)6 
 
X 
X 
X 
X 
X 
Quantitative Immunoglobulins 
X 
 
 
X 
X 
X 
TSH7 
X 
 
 
 
 
 
Coagulation (PT/PTT)8 
X 
 
 
X 
 
 
Flow Cytometry- CLL Panel9 
X 
 
 
X 
X 
X 
Bone marrow biopsy and aspirate10 
X 
 
 
X 
X 
X 
B-cell gene rearrangement – peripheral11 
X 
 
 
 
 
 
CLL FISH Panel16,  
X 
 
 
 
 
 
Zap 70, CD38, IgHV17 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Pregnancy test12 
 
X 
X 
X 
X 
 
Beta2 microglobulin 
X 
 
 
 
 
 
Research blood sample collection13, R 
 
X 
X 
X 
 
 
Research bone marrow aspirate collection14, R 
X 
 
X 
X 
X 
 
Research lymph node aspirate or biopsy collection15, R 
 
X 
X 
X 
 
 
T&B cell quantitation13, R 
 
X 
X 
X 
 
 
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
1. During the first 2 cycles of treatment, patients will have a focused clinical examination weekly for monitoring tumor lysis syndrome (TLS) and tumor 
flare reaction (TFR).  This can be done in collaboration with local MD/referring physician. 
2. Physical exam should measure the spleen and liver noting the maximal distance below the respective costal margins and should record the 
bidimensional diameter of the largest palpable node in each area of involvement including the following sites:  left neck (sub-mandibular, cervical, 
supra-clavicular), right neck (sub-mandibular, cervical, supra-clavicular), left axillary, right axillary, left groin (inguinal, femoral) and right groin 
(inguinal, femoral). 
3. Response assessment: will be done as per IWCLL criteria starting with evaluation at the end of Cycle 2 and every 2 cycles thereafter during treatment.  
The response assessment will be done every cycle during observation. 
4. CT scans should be done as clinically indicated for the management of the patient and in accordance with the IWCLL guidelines. CT scans may be 
done with patient’s primary physician (if outside Mayo Clinic), results of these will be entered in the source document. 
5. EKG testing must be done as clinically indicated ; ECHO if clinically indicated. 
6. Hematology (CBC) / Serum Chemistry: During cycle 1 and 2 (day 8 and 15) will be done at the treating physician’s’ discretion based on patient’s 
clinical needs and/or can be done based on risk for TLS/TFR or for conduct of correlative studies.  In subsequent cycles CBC/chemistry will be done 
prior to beginning of each cycle as standard of care and additional testing will only be done as clinically indicated to be determined by treating 
physician.  Laboratory workup may be done with patient’s primary physician (if outside Mayo Clinic), results of these will be entered in the source 
document. 
7. TSH level will be done at baseline and subsequent testing will be done as clinically indicated and at the discretion of the treating physician. 
8. Coagulation testing: Risk assessment for thrombosis may be done at the treating physician’s discretion. Patients should receive some form of 
thromboprophylaxis as recommended in section 9.8 and monitoring will be done as per standard clinical practice. 
9. Flow Cytometry-CLL Panel: The objective of this is to confirm diagnosis as per standard of care (pretreatment) and during/post treatment to assess 
minimal residual disease. It may be done every 2 cycles starting with Cycle 3 for patients whose ALC is ≤ 5,000 and is not necessary for patients who 
have persistently elevated ALC (>5,000). 
10. Bone marrow biopsy / aspirate: at base line will be done to confirm diagnosis, extent of marrow involvement and subsequently will be done only to 
document complete response as per standard guidelines (see Section 11.0). 
11. B cell gene rearrangement-Peripheral Blood: to assess B-cell clone (at baseline) as per standard of care and then to assess minimal residual disease 
(MRD) or recurrence of clone at the discretion of the treating physician. 
12. Pregnancy test – standard recommendation for patients on lenalidomide therapy. Must be done within 10-14 days of initiation of therapy, 24 hours 
before first dose, weekly for the first 28 days and then every 28 days (or 14 days if menstrual cycles are irregular), and 28 days (or 14 and 28 days if 
menstrual cycles are irregular) after the last dose of lenalidomide. These are recommended for female patients with child bearing potential. Additional 
testing is to be done as clinically indicated and at the discretion of the treating physician. 
13. Blood collected for correlative studies (see Section 14.0) should be collected at baseline; 8 hours, 12 hours and 16 hours post treatment on Cycle 1 Day 
1; Cycle 1 Days 8 and 15; Cycle 2 Days 1, 8 and 15; and Cycle 3 Day 1.  Samples for the T&B cell quantitation will not be collected after Cycle 2 Day 
1. 
14. Mandatory bone marrow aspirate for correlative studies (see Section 14.0) should be collected at baseline, and optionally at Cycle 2 Day 1, Cycle 6 
Day 21, and Cycle 12 Day 21.   


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
15. Optional lymph node aspirate or biopsy for correlative studies (see Section 17.0) should be collected as baseline, within 24 hours of tumor flare, 48-72 
hours after start of tumor flare, 7-10 days after the start of tumor flare, and at resolution of tumor flare. 
16. May be performed anytime within the last year. 
17. Performed at anytime in the past. 
18. A direct bilirubin should be performed at baseline if the total bilirubin is > 1.5 mg/dL. 
R  Research funded. 
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
5.0 
Grouping Factor:  
5.1     Phase:  I vs. II 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Phase I 
 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
 for dose level and to insure that a place on the protocol is 
open to the patient.  
 
6.11 
Registration Procedures 
 
6.111 To register a patient, fax (
) a completed eligibility checklist 
to the Mayo Clinic Cancer Center (MCCC) Registration Office between 
8 a.m. and 4:30 p.m. central time Monday through Friday.   
 
6.2 
Phase II 
 
6.21 
Registration Procedures 
 
6.211 To register a patient, access the Mayo Clinic Cancer Center 
(MCCC) web page and enter the registration/randomization 
application.  The registration/randomization application is 
available 24 hours a day, 7 days a week.  Back up and/or system 
support contact information is available on the Web site.  If 
unable to access the Web site, call the MCCC Registration 
Office at 
 between the hours of 8 a.m. and 5:00 
p.m. Central Time (Monday through Friday). 
 
The instructions for the registration/randomization application are 
available on the MCCC web page 
 
and detail the process for completing and confirming patient registration.  
Prior to initiation of protocol treatment, this process must be completed 
in its entirety and a MCCC subject ID number must be available as noted 
in the instructions.  It is the responsibility of the individual and 
institution registering the patient to confirm the process has been 
successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be 
confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office 
.  If the 
patient was fully registered, the MCCC Registration Office staff can 
access the information from the centralized database and confirm the 
registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
6.3 
Phase I and II 
 
6.31 
Correlative Research 
 
Mandatory: 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.19e and 14.0). 
 
Optional: 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Sections 
14.0 and 17.0). 
 
• 
Patient has/has not given permission to give his/her bone marrow aspirate 
sample for research testing.   
• 
Patient has/has not given permission to give his/her lymph node aspirate or 
biopsy sample for research testing. 
 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 
).  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.34 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of CLL at Mayo. 
• 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.35 
Treatment on this protocol must commence at Mayo Clinic in Florida under the 
supervision of a medical oncologist or hematologist. 
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
6.36 
Treatment cannot begin prior to registration and must begin ≤ 7 days after 
registration. 
 
6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.38 
All required baseline symptoms (see Section 10.6) must be documented and 
graded. 
 
6.39 
Study drug is available on site.  
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule – Cycle length = 28 days Cycles 1-11;  Cycle length = 49-56 days 
Cycle 12 (or last cycle of treatment if patient discontinues treatment before Cycle 12) 
 
7.11 
Phase I (Dose Escalation)   
 
Cycle 1 
Agent 
Dose 
Route 
Day 
Lenalidomide 
As assigned by 
Registration 
Office 
Oral 
1-21 
 
Cycles 2-12* 
Agent 
Dose 
Route 
Day 
Lenalidomide 
Assigned at 
time of 
registration 
Oral 
1-21 
AT-101 
Assigned at 
time of 
registration  
Oral 
1-3 
*Growth factors cannot be used during Cycle 2 due to DLT monitoring. 
 
7.12 
Phase II 
 
Cycle 1 
Agent 
Dose 
Route 
Day 
Lenalidomide 
MTD per Phase 
I findings 
Oral 
1-21 
 
Cycles 2-12 
Agent 
Dose 
Route 
Day 
Lenalidomide 
MTD per Phase 
I findings 
Oral 
1-21 
AT-101 
MTD per Phase 
I findings 
Oral 
1-3 
 


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Protocol Version Date: November 25, 2014 
7.2 
Phase I – determination of Maximum Tolerated Dose (MTD)  
 
 
7.21 
Dose Escalation 
 
Dose level 
Lenalidomide 
AT-101 
-2 
5 mg  
20 mg b.i.d.  
-1 
5 mg  
30 mg b.i.d.  
*1 
 5 mg 
40 mg b.i.d.  
2 
10 mg  
40 mg b.i.d. 
3 
 15 mg 
40 mg b.i.d. 
4 
 20 mg 
40 mg b.i.d. 
 
 
*starting dose level  
 
 
7.211 Treatment by a local medical doctor is not allowed. 
 
7.212  Three patients will be treated at each dose level and observed during the 
first cycle of the combination therapy (i.e., cycle 2: lenalidomide and 
AT-101, up to day 28 of starting the combination) to assess toxicities, 
before new patients are treated.  Doses will not be escalated in any 
individual patient. 
 
 
 
 
7.213 Investigators are to contact the Study Chair as soon as any dose-limiting 
toxicity (DLT) occurs. 
 
7.22 
Definitions of DLT 
 
7.221 For this protocol, dose-limiting toxicity (DLT) will be defined as an 
adverse event at least possibly related to treatment (definitely, probably, 
or possibly related) that occurs in cycle 2 of the study treatment and 
meets the following criteria:  
 
 
 
Toxicity 
DLT Definition 
Hematologic 
ANC ≤ 0.5 x 109/L for more than 14 
days  
 
Febrile neutropenia of any duration 
(ANC <1.0 x 109/L, fever ≥ 38.5°C) 
 
Grade 4 thrombocytopenia or Grade 
3 thrombocytopenia with bleeding or 
any requirement for platelet 
transfusion 
 
Grade 4 anemia, unexplained by 
underlying disease 
Non-hematologic 
Any grade 3 or 4 (except tumor lysis 
syndrome, tumor flare reaction, 
fatigue, nausea, hyperglycemia in 
diabetic patients) 
 
 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1  
Dose Levels (Based on Adverse Events in Tables 8.2 and 8.3) 
 
Dose 
Level 
Lenalidomide 
AT-101 
-2 
5 mg  
20 mg b.i.d.  
-1 
5 mg  
30 mg b.i.d.  
1* 
 5 mg 
40 mg b.i.d.  
2 
10 mg  
40 mg b.i.d. 
3 
 15 mg 
40 mg b.i.d. 
4 
 20 mg 
40 mg b.i.d. 
* Dose level 1 refers to the starting dose. 
 
Omit = The current dose(s) for the specified drug(s) during a cycle is skipped.  The patient  
does not make up the omitted dose(s) at a later time 
 
Hold/Delay =  The current dose(s) of all drugs during a cycle is delayed.  The patient does  
make up the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
 
Discontinue = The specified drug(s) are totally stopped. 
 
8.2 
Lenalidomide 
 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥ 1,000/μL; 
• 
The platelet count is ≥ 25,000/μL; 
• 
Any lenalidomide-related allergic reaction/hypersensitivity or sinus bradycardia/ 
other cardiac arrhythmia adverse event that may have occurred has resolved to ≤ 
grade 1 severity; 
• 
Any other lenalidomide-related adverse event that may have occurred has resolved to 
≤ grade 2 severity. 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of lenalidomide will not be initiated until the toxicity has 
resolved as described above.  If lenalidomide dosing was omitted during the previous 
cycle and was restarted with a one-level dose reduction without requiring an interruption 
for the remainder of the cycle, then that reduced dose level will be initiated on Day 1 of 
the new cycle. If lenalidomide dosing was omitted for the remainder of the previous 
cycle or if the new cycle is delayed due to toxicity newly encountered on the 
scheduled Day 1, then the new cycle will be started with a one-level dose reduction.   
 
If either drug is discontinued, patient will come off treatment and go to event 
monitoring. 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENTS  (Days 2-28) 
 
 
 
 
 
Investigations 
Platelet count decreased*: 
(Platelets < 10,000/mm3) 
Lenalidomide 
• Omit dose. 
• Follow CBC weekly. 
• If thrombocytopenia resolves to ≤ 
grade 3 restart lenalidomide at the 
same dose level.  
• If thrombocytopenia < 10,000/mm3 
recurs, reduce dose by one dose level 
(5 mg) and continue therapy when 
platelet count ≥ 25,000/mm3. 
Grade 4 Neutrophil count 
decreased* 
 
 
• Omit dose. 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤ grade 
2, resume dose at same level with 
GCSF support. 
Blood and lymphatic 
system disorders 
≥ Grade 3 Febrile 
neutropenia 
• Omit dose. 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤ grade 
2, resume dose at same level with 
GCSF support. 
 
 
Cardiac Disorders 
Sinus bradycardia/ other 
cardiac Arrhythmia 
Grade 2 
• Omit dose.  Follow at least weekly. 
• If the toxicity resolves to ≤ grade 1, 
reduce dose by one dose level (5mg) 
and continue therapy. 
≥ Grade 3 
• Discontinue study treatment and go to 
event monitoring.  
Vascular disorders 
thromboembolic event 
≥ Grade 3 
• Omit dose and start anticoagulation; 
restart at investigator’s discretion 
(maintain dose level). 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENTS  (Days 2-28) 
 
 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
Lenalidomide 
• Omit dose.  Follow at least weekly. 
• If the toxicity resolves to ≤ grade 1, 
reduce dose by 5 mg and continue 
therapy. 
Anaphylaxis 
Grade 4 
• Discontinue study treatment and go to 
event monitoring. 
 
 
 
Skin and 
subcutaneous tissue 
disorders 
Erythema multiforme ≥ 
Grade 3 
• Discontinue study treatment and go to 
event monitoring. 
Skin ulceration ≥ Grade 
2 
• Discontinue study treatment and go to 
event monitoring. 
Other: Non-blistering 
rash  Grade 3 
• If Grade 3 omit dose.  Follow weekly. 
• If the toxicity resolves to ≤ grade 2 
continue therapy. 
Other: Non-blistering 
rash  Grade 4 
• Discontinue study treatment and go to 
event monitoring. 
Other 
Non-hematologic 
toxicity assessed as 
lenalidomide related ≥ 
Grade 3 
• Omit dose.  Follow at least weekly. 
• If the toxicity resolves to ≤ grade 2, 
implement one dose reduction step and 
continue therapy. 
* use IWCLL/Hallek, December 2008 criteria (see Appendix V)  
 
NOTE: Subjects who cannot tolerate the minimum dose 5 mg daily on days 1 – 21 of a 28 day 
cycle, are to be discontinued from the treatment phase of the study  and go to event monitoring. 
 
Note: Dose modification schedule as outlined in the table above will be applicable to all patients 
enrolled on the study.  This schedule will not be applicable to patients during the two cycles of 
the combination therapy of the patients enrolled on the phase I portion of the study to clearly 
define MTD.  Once patients on the phase I portion of the study have completed cycle #2 (1st 
combination cycle) they may be managed based on the dose modification criteria outlined in the 
table above. Dose modification due to toxicity will be based on dose de-escalation in 5 mg 
increments from the maximum dose obtained for the individual patient.  The optimum dose in any 
individual patient may be determined by the investigator based on managing toxicity and 
maximizing response.  The maximum dose of lenalidomide permitted will not exceed the MTD 
determined in the phase I portion of the study and is not to exceed 20 mg daily on days 1 – 21 of 
a 28 day cycle and the minimum dose permitted is 5 mg daily on days 1 – 21 of a 28 day cycle. 
 
Dose re-escalation: For patients who are dose reduced either for disease or drug related 
toxicities, lenalidomide dose re-escalation can be considered provided all toxicity has resolved to 
≤ Grade 1. Patients can be started at minimum of 5mg PO daily on days 1 – 21 of a 28 day cycle 
and the dose titrated up at 5mg increments weekly to the target dose not to exceed the MTD 
determined in the phase I portion of the study.  The rate of escalation is at the PI discretion based 
on patient tolerability and concern for tumor lysis syndrome.  


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
 
8.3 
AT-101 
 
During the study period it is the goal to prescribe the fully intended dose of AT-101. It is 
expected that toxicity of AT-101 can be solved with appropriate measures. However, in 
case of severe toxicity (grade ≥ 3) attributed (possibly, probably or definitively) to AT-
101, treatment will be held for a maximum of 8 weeks. If toxicities resolve to ≤ grade 1, 
patients may resume treatment. Patients who are resumed on treatment will be started at a 
lower dose of AT-101 (25% dose reduction or 30mg BID); if the toxicity recurs (grade ≥ 
3) then one more dose reduction (50% dose reduction or 20mg BID) will be allowed 
(upon resolution of toxicity ≤ grade 2).  If toxicity recurs ≥ grade 3, patients will be 
removed from the study treatment and go to event monitoring.  
 
Note: No dose reduction is allowed in cycle #2 as this is the MTD defining cycle. 
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 unless 
otherwise specified   
CTCAE 
System/Organ/Class 
(SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENTS  (Days 2-3) 
Gastrointestinal 
disorders 
≥ Grade 2 Nausea  
 
 
AT-101 
For any of these events that last longer 
than 48 hours, AT-101 should be omitted 
and the following actions are 
recommended: 
•  Physical examination, including 
assessment of vital signs 
•  Screening abdominal radiography to 
include an abdominal series to 
exclude ileus, small bowel obstruction 
(SBO), or pneumatosis intestinalis. 
•  Consideration for obtaining a CT scan 
with contrast of the abdomen should 
be made based on clinical judgment 
• If ileus, non-mechanical SBO, or 
pneumatosis intestinalis are excluded, 
AT-101 dosing may be reinstated. If a 
patient is determined to have ileus, 
SBO, or pneumatosis intestinalis, AT-
101 dosing should be permanently 
discontinued and expectant 
management with supportive care is 
recommended, unless clinical signs or 
symptoms are present that suggest 
septicemia or abdominal catastrophe 
that warrants surgical management. 
≥ Grade 2 Vomiting 
Any Grade Abdominal 
pain 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Antiemetics may be used at the discretion of the attending physician. 
 
9.2 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  Growth factors cannot be used 
during Cycle 2 of the Phase I portion due to DLT monitoring.  The use of growth factors 
should follow published guidelines of the American Society of Clinical Oncology (42) 
Update of Recommendations for the Use of Hematopoietic Colony-Stimulating Factors: 
Evidence-Based, Clinical Practice Guidelines.  J Clin Oncol 18(20): 3558-3585, 2000.  
 
9.3 
Patients should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, and antiemetics when appropriate.  Any blood transfusions 
administered must be irradiated blood products to reduce risk of transfusion 
mediated graft versus host disease in CLL patients receiving T-cell suppressive 
therapy.  Leukocyte reduction of all blood products for patients on protocol is 
also required. All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment 
administration until 30 days after the final dose will be recorded in the medical 
records. 
 
9.4 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.5 
Tumor Lysis Syndrome (TLS) Prophylaxis and Treatment 
Subjects must receive Allopurinol 300 mg/day (or an equivalent standard agent for 
prevention of hyperuricemia) orally for the first two weeks of the first cycle of protocol 
therapy. Allopurinol may be continued after the first two weeks at the investigator’s 
discretion and as clinically indicated. Subjects should be observed closely for signs and 
symptoms of TLS during the initial cycle of therapy. Subjects should be encouraged to 
drink an abundant amount of fluid prior to treatment. Subjects should maintain adequate 
hydration and urine output. 
 
9.6 
Tumor Flare Reaction (TFR) 
Patients may not receive any prophylaxis for TFR. We do not anticipate severe (grade 4) 
TFR. It is to be noted that in our previous clinical trial (using 25mg PO QD) no grade 4 
TFR was observed. Also, as occurrence of the TFR can positively impact response and 
progression free survival (PFS) (Chanan-Khan et al Cancer 117(10) 2127-35), steroid 
prophylaxis for TFR will not be used.  We recommend the following management plan 
for TFR: 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
Grade 1-2 TFR:  Grade 1 defined as mild pain not interfering with function; grade 2 
defined as moderate pain; pain or analgesics interfering with function, but not interfering 
with activities of daily living (ADL). Patients can be treated with (a) non-steroidal anti-
inflammatory agents (preferred agent - ibuprofen 400-600mg PO Q8 hours) to decrease 
inflammatory response and / or (b) morphine sulphate (or equivalent analgesic) to control 
flare associated pain.   
 
Grade 3 TFR:  Defined as severe pain; pain or analgesics interfering with function and 
interfering with ADL. Patients will be treated with (a) non-steroidal anti-inflammatory 
agents (preferred agent - ibuprofen 400-600mg PO Q8 hours) to decrease inflammatory 
response and (b) morphine sulphate (or equivalent analgesic) to control flare associated 
pain.  Also, (c) low-dose steroid treatment (preferred agent prednisone 20mg PO QD x 7 
days and then 10mg PO QD x 7 days) can be added to this regimen at treating physician’s 
discretion and as clinically indicated.  
 
Grade 4 TFR:  Defined as disabling.  (a) treatment will be stopped until TFR grade is ≤ 
grade 1.  (b) steroid treatment will be initiated (preferred agent prednisone 20mg PO QD 
x 7 days and then 10mg PO QD x 7 days) can be added to this regimen at treating 
physician’s discretion and as clinically indicated. High dose steroid (Prednisone 60-
100mg PO QD x 5 days and then tapering doses, alternatively medrol pack can be used) 
maybe initiated as clinically indicated and at treating physician’s discretion.  (c) non-
steroidal anti-inflammatory agents (preferred agent - ibuprofen 400-600mg PO Q8 hours) 
to decrease inflammatory response and morphine sulphate (or equivalent analgesic) to 
control flare associated pain may be added at treating physician’s discretion. 
 
9.7 
Lymphadenitis (cytokine release syndrome) 
Some subjects with CLL have experienced lymphadenitis characterized by swelling of 
the lymph nodes, fever, and pain. This syndrome is likely a result of cytokine release. If 
these symptoms occur, subjects should be treated with methylprednisolone 50 mg IV or 
dexamethasone 10 mg IV (or equivalent dose of corticosteroid therapy, either IV or PO) 
at least once daily until symptoms resolve.  
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
9.8 
Anticoagulation prophylaxis:  Due to high-risk of thromboembolism with lenalidomide 
all subjects will receive thromboprophylaxis either with:  
 
 
 
(a) warfarin 1 mg (for <70 kg body weight) and 2 mg (>70 kg body weight) orally QD 
while on lenalidomide therapy either alone or in combination phase.  Full anti-
coagulation may be done if in investigators’ assessment there is a higher risk of 
developing a venous thromboembolic event. Warfarin should be stopped if platelet count 
is < 50,000 and should be resumed once platelet counts increase and are above >50,000. 
Patients who are on full therapeutic dose of warfarin or low-molecular heparin for prior 
episode of DVT or other indications can be enrolled and treated on this protocol but will 
not require low-dose warfarin prophylaxis. Patients developing a DVT/PE while on this 
study should have their treatment held and receive full therapeutic anticoagulation either 
with warfarin (target INR 2-3) or low-molecular weight heparin as per standard clinical 
practice.  Once therapeutic level of anticoagulation is achieved, these patients can resume 
therapy on the study.  Anticoagulation in these patients should be continued throughout 
the duration of therapy and can be stopped 1 week after the last dose of lenalidomide. 
(b) Low-dose aspirin (81 mg PO QD) can be used as an alternative strategy. 
Selection of either (a) vs. (b) will be at the treating physician’s discretion.  
 
9.9a 
Contraindicated medications: Patient should not be allowed to take concurrent oral 
iron supplements (including nutritional supplements containing iron) while taking AT-
101.  
 
9.9b 
Pneumocystis jiroveci prophylaxis: Co-trimoxazole (Bactrim®) SS, 1 tablet by mouth 
daily beginning Day 1 and continued for the duration of treatment until one month 
following completion of treatment. Co-trimoxazole intolerant patients will receive 
dapsone 100 mg per day by mouth or atovaquone 1,500 mg per day by mouth for the 
same period.  
 
9.9c 
Herpes Simplex and Herpes Zoster prophylaxis: Acyclovir 400 mg by mouth twice a 
day OR valacyclovir 500 mg by mouth daily beginning Day 1 and continued for the 
duration of treatment until one month following completion of treatment.  Substitution 
with comparable doses of famciclovir is allowed for the same period. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
Section 10.5).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.6 and 
18.0). 
 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same 
as serious AE which is defined in the table in Section 10.4. 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol and the study specific 
consent form. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol and the study specific consent form. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 






MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
events must still be reported through the routine reporting mechanisms [i.e. Nadir/adverse 
events form]; see footnote 1):  
 
System Organ Class (SOC) 
 
Adverse event/ Symptoms 
 
CTCAE Grade at which the 
event will not be 
expeditedly reported 1. 
Blood and lymphatic system 
disorders 
Anemia 
≤4 
Investigations 
White blood cell decreased 
≤4 
Lymphocyte count decreased  
≤4 
Neutrophil count decreased 
≤4 
Platelet count decreased 
≤4 
 
1  These exceptions only apply if the adverse event does not result in hospitalization.  If 
the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirments must be followed.   
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
10.5 
Other Required Reporting 
 
10.51 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
10.52   Death 
 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by cessation of life 
during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be attributed to a CTCAE 
term associated with Grade 5. 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
• 
Sudden death NOS:  A sudden (defined as instant or within one hour 
of the onset of symptoms) or an unobserved cessation of life that 
cannot be attributed to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
10.53 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE be reported. Three options are available to describe the 
event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
 
 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.54 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting. 
 
10.55 Pregnancies 
 
Pregnancies occurring while the subject is on study drug or within 4 weeks after 
the subject’s last dose of study drug are considered immediately reportable 
events.  If the subject is on study drug the study drug is to be discontinued 
immediately and the subject is to be instructed to return any unused portion of the 
study drug to the Investigator.  The pregnancy must be reported to the Safety 
Monitor within 24 hours of the Investigator’s knowledge of the pregnancy by 
phone and facsimile using the SAE Form. 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
The Investigator will follow the subject until completion of the pregnancy, and 
must notify the Safety Monitor of the outcome within 5 days or as specified 
below.  The Investigator will provide this information as a follow-up to the initial 
SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an aborted 
fetus is to be documented], stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures for reporting SAEs (i.e., report the 
event to the Safety Monitor by telephone and facsimile within 24 hours of the 
Investigator’s knowledge of the event). 
 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to the study drug should 
also be reported. 
 
In the case of a live “normal” birth, the Safety Monitor should be advised as soon 
as the information is available. 
 
10.6 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ Class 
(SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Investigations 
Platelet count decreased* 
 
X 
 
X 
 
Blood and lymphatic 
system disorders 
Anemia* 
X 
X 
Gastrointestinal disorders 
Constipation 
X 
X 
Ileus 
 
X 
* Grading will be performed by the study statisticians at the time of analysis based on the CLL 
toxicity grading scale for blood counts in Appendix V.  Anemia grade per CTCAE will also be 
recorded for reporting purposes. 
 
10.61 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.6: 
 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613  Grade 5 AEs (Deaths) 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
10.6131  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.6132 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.62   Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
11.0 
Treatment Evaluation  
 
Note:  Formal response evaluation should occur every 2 cycles during treatment, with the 
first response evaluation occurring at the end of cycle 2.  Formal response evaluation should 
occur every cycle during observation.  Objective status should be classified as PD vs. Not 
PD on cycles when a formal response evaluation does not occur.   
 
11.1 
Schedule of evaluations:  For the purposes of this study, patients should be reevaluated 
for progression every 28 days during therapy with lenalidomide and AT-101.  Formal 
response evaluation will occur every 2 cycles, with the first formal response evaluation 
occurring at the end of cycle 2.  However, patients will be evaluated prior to each cycle 
of therapy to identify individuals who have experienced disease progression.  Prior to the 
first formal response evaluation, baseline on study measurements will be used to 
determine disease progression (e.g. not cycle by cycle comparisons).  Once patients 
undergo formal response evaluation, the nadir value at either baseline or time of response 
evaluation will be used for evaluating future disease progression. In addition to a baseline 
scan, confirmatory scans should also be obtained as needed to document objective 
response at sites of non-palpable lymphadenopathy or organomegaly as indicated in 
Section 4 or as needed clinically.   
 
NOTE: Information from CT scans is not considered in the standard classification of 
response. 
 
11.2 
Definitions 
 
The NCI Working Group criteria59 will be used to assess response to therapy.  
 
11.21 COMPLETE RESPONSE (CR) requires all of the following for a period of at least  
2 months.  The first formal response evaluation for CR should occur no sooner than 
the end of cycle 2.   
 
11.211 Absence of lymphadenopathy (e.g. lymph nodes >1.5 cm) by physical 
examination. 
 
11.212 No hepatomegaly or splenomegaly by physical examination. 
 


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11.213 Absence of constitutional symptoms. 
 
11.214 CBC demonstrating: 
• 
Neutrophils >1500/ul. 
• 
Platelets >100,000/ul (untransfused). 
• 
Hemoglobin >11.0 gm/dl (untransfused). 
• 
Peripheral blood lymphocytes <4000/uL. 
 
Note: Patients who fulfill all criteria for a CR but who have a persistent 
anemia, thrombocytopenia, or neutropenia related to drug toxicity rather 
than residual CLL will be classified as CR with incomplete marrow 
recovery (CRi) according to the international criteria59. 
 
11.215 Bone marrow aspirate and biopsy should be performed within two 
month after documentation of clinical and laboratory evidence of a 
complete response to document that a complete response (CR) has been 
achieved.  The marrow sample should ideally be at least normocellular 
with <30% of nucleated cells being lymphocytes.  Samples are to be 
analyzed by a pathologist and the presence or absence of nodules noted.  
Repeat bone marrow aspirate and biopsy are not necessary to document 
sustained CR. 
 
In a subset of patients who are otherwise in a complete response, bone 
marrow nodules can be identified histologically.  In such cases, special 
stains will be performed to determine whether such nodules represent 
“regenerative nodules” or residual “clonal nodules”.  The presence of 
regenerative nodules is consistent with CR while the presence of residual 
clonal nodules will be classified as an nPR (nodular PR) which is a sub-
classification of PR. 
 
 
 
 
 
 
Note:  In a patient who achieves clinical and laboratory evidence of a 
complete response, the objective status should be recorded as a CCR on 
the cycle where the formal response evaluation occurred until a bone 
marrow biopsy and aspirate have been performed.  At that time, the 
objective status should be amended to classify the patient as a CR, CRi, 
or nPR on the cycle where the formal response evaluation occurred. 
 
11.216 Patients who have clinical and laboratory evidence of CR but who have 
not yet had a bone marrow biopsy to distinguish between CR and nPR 
will be classified as having a Complete Clinical Response (CCR) until 
the marrow biopsy is obtained. 
 
11.217 In some settings MRD assays may be considered as a surrogate of 
response as discussed in section 11.3.  No other laboratory assays (e.g., 
quantitative immunoglobulins) will be used currently as an index for 
response but will be recorded for clinical correlations. 
 
11.218 For patients whose only measurable disease at the time of enrollment is 
on CT scan (i.e. SLL with no palpable nodes), a CT scan is required 
before classifying patients a CR. 


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11.22 PARTIAL RESPONSE (PR) requires the patient exhibits at least two of the features 
in Sections 11.221, 11.222, and 11.223 below (if abnormal prior to therapy) as well 
as one or more of the remaining features (Sections 11.224, 11.225, 11.226) for at 
least 2 months.  In addition to the parameters listed below, the presence or absence of 
constitutional symptoms will be recorded.  The first formal response evaluation for 
PR should occur no sooner than the end of cycle 2.   
 
11.221 ≥ 50% decrease in peripheral blood lymphocyte count from the 
pretreatment baseline value. 
 
11.222 ≥ 50% reduction in the sum of the products of the maximal perpendicular 
diameters of the largest measured node or nodal masses in the right and 
left cervical, axillary, and inguinal lymph node regions on physical 
examination.  
 
11.223 ≥ 50% reduction in size of liver and/or spleen as measured by physical 
exam noting the maximal distance below the respective costal margins of 
palpable hepatosplenomegaly during rest.   
 
11.224 Neutrophils >1500/ul or 50% improvement over baseline. 
 
11.225 Platelets >100,000/ul or 50% increase over baseline. 
 
11.226  Hemoglobin >11.0 gm/dl or 50% increase over baseline without transfusions. 
 
11.227 For patients whose only measurable disease at the time of enrollment is on CT 
scan (i.e. SLL with no palpable nodes), a CT scan demonstrating > 50% 
reduction of target nodes enlarged at baseline is required before classifying 
patients a PR. 
 
11.228 For patients whose only measurable disease at the time of enrollment is 
on CT scan (i.e. SLL with no palpable nodes), a CT scan is required 
before classifying patients PR. 
 
11.23 PROGRESSION (PD):  Patients will receive protocol therapy unless they have 
evidence of disease progression according to the NCI criteria3 as evidenced by: 
 
11.231 ≥ 50% increase in the sum of the products of at least 2 lymph nodes on 2 
consecutive determinations 2 weeks apart (at least one node must be ≥2 
cm) or the appearance of new palpable lymph nodes >1.5 cm not due to a 
tumor flare.  Enlargements or the appearance of new nodes due to a 
tumor flare do NOT qualify as progression.   
 
11.232 ≥ 50% increase in the size of the liver and/or spleen as determined by 
measurement below the respective costal margin on 2 consecutive 
determinations 2 weeks apart and with a minimum of a ≥ 2 cm increase 
in size from baseline; or appearance of hepatomegaly or splenomegaly 
which was not previously present at baseline and not due to a tumor 
flare. 


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Protocol Version Date: November 25, 2014 
 
11.233 Transformation to a more aggressive histology (e.g. Richter’s 
transformation). 
 
11.234 ≥ 50% increase in the absolute number of circulating lymphocytes NOT 
due to infection or tumor flare (taking as reference for progressive 
disease the smallest absolute lymphocyte count recorded since the 
treatment started).  The absolute lymphocyte count must be at least 
5000/mm3 to qualify as disease progression. 
 
11.235 In the absence of progression as defined by 1, 2, 3, or 4 above, the 
presence of a ≥ 2 g/dl decrease in HGB, or ≥ 50% decrease in platelet 
count, or absolute neutrophil count will NOT exclude a patient from 
continuing the study.  Work-up of such decreases to exclude auto-
immune hemolytic anemia, pure red cell aplasia, or idiopathic 
thrombocytopenic purpura (ITP) should be considered. 
 
11.236 For patients who achieve a CR or nodular PR, progression will be 
defined as recurrence of circulating leukemia cell clone and an ALC 
>5000 or recurrence of adenopathy >1.5 cm not due to a tumor flare. 
 
11.24 STABLE DISEASE (SD): Patients who do not meet criteria for CR, CRi, nPR, 
CCR, PR, or PD will be classified as having “stable disease”.  The first formal 
response evaluation should occur no sooner than the end of cycle 2.   
 
11.25    Not PD:   The patient was evaluated for progression only this cycle and a formal 
response evaluation did not occur.  The patient did not meet the criteria for 
progression per section 11.23.   
 
Note:  Formal response evaluation should occur every 2 cycles during 
treatment, with the first response evaluation occurring at the end of cycle 2.  
Formal response evaluation should occur every cycle during observation.  
Objective status should be classified as PD vs. Not PD on cycles when a 
formal response evaluation does not occur.   
 
11.3  
EVALUATION OF MINIMAL RESIDUAL DISEASE (MRD):  MRD will be assessed 
by flow cytometry and/or PCR for patients who achieve a CR/nPR/CRi.  
 


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Protocol Version Date: November 25, 2014 
11.4 
Summary Definition of objective response for patients with B–CLL 
 
 
CCR1 
CR2 
CRi3 
nPR4 
PR5 
PD6 
PHYSICAL EXAM  
 
Nodes7 
None 
None 
None 
None 
≥50%  
≥50% , new nodes 
 
Liver/spleen8 
Not palpable Not palpable 
Not palpable 
Not palpable 
≥50%  
≥50% , newly 
palpable 
 
Symptoms 
None 
None 
None 
None 
N/A 
N/A 
PERIPHERAL BLOOD 
 
 
ANC 
>1500/µL 
>1500/µL 
See footnote 3 
>1500/µL 
>1500/µL or >50% 
improvement from baseline 
See footnote 6 
 
Platelets 
>100,000/ 
µL 
>100,000/µL 
See footnote 3 
>100,000/µL 
>100,00/µL or >50% 
improvement from baseline 
See footnote 6 
 
Hemoglobin 
>11.0 g/dL 
without 
transfusion 
>11.0 g/dL 
without 
transfusion 
See footnote 3 
>11.0 g/dL without 
transfusion 
>11.0 g/dL or >50% 
improvement from baseline 
without transfusion 
See footnote 6 
 
Lymphocytes 
<4000/µL 
<4000/µL 
<4000/µL 
<4000/µL 
≥50%  
≥50%  to at least 
5,000/µL 
BONE MARROW 
N/A 
<30% 
lymphocytes; no 
nodules 
<30% 
lymphocytes; no 
nodules 
bone marrow 
nodules4 
N/A 
N/A 
1. 
Clinical complete response (CCR) requires fulfillment of all physical exam and peripheral blood criteria as noted in the table above.  No bone marrow biopsy is required to call a patient a CCR; however, 
patients who achieve a CR/nPR/CRi should have a bone marrow within one month of the formal response evaluation where clinical and laboratory evidence of complete response was first seen as instructed in 
the test schedule to confirm CR.   
2. 
Complete response (CR) requires fulfillment of all physical exam and peripheral blood criteria for a duration of ≥2 months.  A bone marrow aspirate and biopsy are required to document the response as a 
complete within one month of the formal response evaluation where clinical and laboratory evidence of complete response was first seen (see Section 11.21).  
3.      Patients who fulfill all criteria for a CR but who have a persistent anemia, thrombocytopenia, or neutropenia related to drug toxicity rather than residual CLL will be classified as CR with incomplete marrow 
recovery (CRi).  
4. 
Nodular partial response (nPR) is essentially a patient in who it appeared that CR had been obtained but nodules are present in the bone marrow.  It requires fulfillment of all physical exam and peripheral blood 
criteria for CR; however, when the bone marrow is done to confirm CR, nodules of malignant lymphocytes are found.  See Section 11.215 regarding the distinction between clonal and regenerative nodules.  
5. 
Partial response (PR) requires fulfillment of at least two of the above-noted decrease in circulating lymphocytes, regression in adenopathy and regression in hepatosplenomegaly, and at least one other parameter 
listed above for a duration of ≥ 2 months.  See Section 11 22. 
 
Footnotes continued on next page. 
 
 


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6. 
Progression:  Fulfilling the criteria as noted in section 11.23.  Prior to the formal response evaluation, baseline on study measurements will be used to determine disease progression (e.g. not cycle by cycle 
comparisons).  Once patients undergo formal response evaluation, the nadir value at either baseline or time of response will be used for evaluating future disease progression. In the absence of other indices of 
clinical progression, the presence of a ≥2 g/dL decrease in hemoglobin or a ≥50% decrease in platelet count and/or absolute neutrophil count will not exclude a patient from continuing on the study. Although not 
mandatory, bone marrow aspirate and biopsy are strongly encouraged to better define the cause of the suppressed counts (i.e. treatment- versus disease-related). 
7. 
Measurement of lymphadenopathy will be determined on physical exam by adding the sum of the products of the maximal perpendicular diameters of measured lesion(s).  No simultaneous increase in the size of 
any lesions or the appearance of any new lesions may occur for more than 2 consecutive cycles.  Minor fluctuations are acceptable as long as they don’t exceed 50% of previous measurement.  However, if they 
do exceed 50% of the previous measurement it should be held for 2 consecutive cycles to rule out the possibility of nodes that wax and wane.  For purposes of determining CCR and nPR, all nodes on physical 
exam need to be ≤ 1.5 cm in maximal dimension or documented to be free of CLL by biopsy. NOTE: Information from CT scans regarding lymphadenopathy is not considered in the standard classification of 
response with the exception of the patients fitting criteria of section 11.218 and 11.228. 
8.  
Measurement of hepatosplenomegaly will be determined by noting the maximal distance below the respective costal margins of palpable hepatosplenomegaly during rest (e.g., not during deep inspiration). 
NOTE: Information from CT scans regarding hepatosplenomegaly is not considered in the standard classification of response with the exception of the patients fitting criteria of section 11.218 and 11.228. 


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Protocol Version Date: November 25, 2014 
12.0 
Descriptive Factors 
 
12.1 
Rai Stage:  0 vs. 1 vs. 2 vs. 3 vs. 4. (Appendix II) 
 
12.2 
CD38+ expression:  Positive (≥30%) vs. negative (<30%). 
 
12.3 
Chromosomal anomalies as detected by FISH:  13q- vs. 12+ vs. 11q- vs. 17p- vs. other 
abnormality vs. normal karyotype. 
 
12.4 
IgVH mutation status:  Mutated (≥2%) vs. unmutated (<2%) vs. indeterminate.  
 
12.5 
ZAP-70 expression:  Positive (≥20%) vs. negative (<20%).  
 
12.6  
Dose level (to be  assigned by the Registration Office): -2 vs. -1 vs. 1 vs. 2 vs. 3 .vs. 4. 
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1  
If the patient develops PD at any time during active treatment, unacceptable adverse 
events,  or patient refuses all further study participation, study treatment will be 
discontinued and the patient will go directly to event monitoring. Patients will then be 
followed in event monitoring per Section 18.0. 
 
13.2  
Patients not progressing on active treatment will continue treatment per protocol up to a 
maximum of 12 cycles. After the completion of 12 cycles, the patient will go to 
observation (maximum duration of observation 2 years). 
 
13.3 
Phase I Only:   If a patient fails to complete the first two cycles of treatment for reasons 
other than toxicity, the patient will be regarded as inevaluable and will be replaced.    
 
13.4 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
• 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. No further data submission 
is necessary. 
 
13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol. 
 


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13.6 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 


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Protocol Version Date: November 25, 2014 
 
14.0 
Body Fluid Biospecimens   
 
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
14.11 Peripheral Blood 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to 
be 
collected) 
Baseline  
Cycle 1 Day 1: 
8 hours, 12 
hours, & 16 
hours post 
treatment 
Cycle 
1 Days 
8 & 15 
Cycle 2 
Days 1, 
8, & 15 
Cycle 3 
Day 1 
Immune cellular 
microenvironment1  
Mandatory 
Peripheral 
Blood 
Green top  
5 mL (1-2) 
X 
X 
X 
X 
(Day 1 
only) 
 
Effect of 
lenalidomide & AT-
101 on molecular 
targets 
Mandatory 
Peripheral 
Blood 
Green top 
5 mL (1-2) 
X 
X (prior to 
treatment only) 
X 
X 
X 
1. Samples for T and NK cells will be sent to routine clinical lab for testing and charged to the study.


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
14.12 Bone Marrow Aspirate 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or 
Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collectio
n Tube 
(color of 
tube top) 
Volume 
to collect 
per tube 
(# of 
tubes to 
be 
collected) 
Visit 1 
(Baseline) 
Visit 2 
(Cycle 2 
Day 1) 
Visit 3 
(Cycle 7 
Day 1) 
Visit 4 (At 
end of 
treatment) 
Immune cellular 
microenvironment 
and Effect of 
lenalidomide and 
AT-101 on 
molecular targets 
Mandatory at 
Baseline and 
all other 
timepoints 
are optional 
Bone 
marrow 
aspirate 
Green top  
3 mL (1) 
X 
X 
X 
X 




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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
be registered; a maximum 28-day supply may be dispensed; a new prescription is 
required each time it is filled; pregnancy testing is required for females of 
childbearing potential. 
 
15.13 Preparation, storage, and stability: Store oral capsules at controlled 
room temperature between 15ºC and 30ºC (59 ºF and 86 ºF). Refer to 
labeling on the bottle for expiration date of the commercial tablets. 
  
15.14 Administration:  Refer to the treatment section for specific administration 
instructions. Administer with water. Swallow capsule whole; do not break, open, 
or chew. 
 
 
15.15 Pharmacokinetic information: 
Absorption: Rapid 
Metabolism: Approximately two-thirds of Lenalidomide is eliminated 
unchanged through urinary excretion.  
Protein binding: ~30% 
Time to peak, plasma: Healthy volunteers: 0.6-1.5 hours; Myeloma 
patients: 0.5-4 hours 
Half-life elimination: ~3 hours 
Excretion: Urine (~67% as unchanged drug) 
 
 
15.16 Potential Drug Interactions: 
Increased Effect/Toxicity: Abatacept and Anakinra may increase the risk 
of serious infection when used in combination with Lenalidomide. 
Lenalidomide may increase the risk of infections associated with vaccines 
(live organism). 
Decreased Effect: Lenalidomide may decrease the effect of vaccines 
(dead organisms). 
Herb/Nutraceutical Interactions: Avoid echinacea (has 
immunostimulant properties; consider therapy modifications). 
 
15.17 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
 
Boxed Warnings:  
1. Potential for human birth defects 
2. Hematologic toxicity (neutropenia and thrombocytopenia) 
3. Deep Venous Thrombosis and Pulmonary Embolism 
 
Common known potential toxicities, > 10%:   
Cardiovascular: Peripheral edema  
Central nervous system: Fatigue, pyrexia, dizziness, headache 
Dermatologic: Pruritus, rash, dry skin 
Endocrine & metabolic: Hyperglycemia, hypokalemia 
Gastrointestinal: Diarrhea, constipation, nausea, weight loss, dyspepsia, 
anorexia, taste perversion, abdominal pain 
Genitourinary: Urinary tract infection 


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MCCC Addendum 1 
 
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Hematologic: Thrombocytopenia, neutropenia, anemia, myelosuppression 
is dose-dependent and reversible with treatment interruption and/or dose 
reduction 
Neuromuscular & skeletal: Muscle cramp, arthralgia, back pain, tremor, 
weakness, paresthesia, limb pain 
Ocular: Blurred vision 
Respiratory: Nasopharyngitis, cough, dyspnea, pharyngitis, epistaxis, 
upper respiratory infection, pneumonia 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Edema, deep vein thrombosis, hypertension, chest pain, 
palpitation, atrial fibrillation, syncope 
Central nervous system: Insomnia, hypoesthesia, pain, depression 
Dermatologic: Brusing, cellulitis, erythema 
Endocrine & metabolic: Hypothyroidism, hypomagnesemia, hypocalcemia 
Gastrointestinal: Vomiting, xerostomia, loose stools 
Genitourinary: Dysuria 
Hematologic: Leukopenia, febrile neutropenia, Lymphopenia 
Hepatic: ALT increased 
Neuromuscular & skeletal: Myalgia, rigors, neuropathy 
Respiratory: Sinusitis, rhinitis, bronchitis, pulmonary embolism 
Miscellaneous: Night sweats, diaphoresis 
 
Rare known potential toxicities, <1% (Limited to important or life-
threatening):  
Angioedema, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 
Tumor Lysis Syndrome 
 
15.18 Drug procurement:  As a requirement of the REMS program, access to 
Lenalidomide is restriced. Lenalidomide is approved for marketing only under a FDA 
approved, restricted distribution program called REVLIMID REMS  
(www.REVLIMIDREMS.com) formerly known as the RevAssist program. Physicians, 
pharmacies, and patients must be registered; a maximum 28-day supply may be 
dispensed; a new prescription is required each time it is filled; pregnancy testing is 
required for females of childbearing potential. 
 
15.19 Nursing Guidelines:  
 
15.191 Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. 
Instruct patient to report any unusual bruising or bleeding 
(thrombocytopenia); signs and symptoms of infection (neutropenia); and 
energy conserving lifestyle (anemia). 
 
15.192 Lenalidomide can have thrombotic adverse events (i.e DVT and PE). 
Instruct patient to report any limb swelling or pain, and to seek medical 
attention for shortness of breath or chest pain. 
 
15.193 Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
therapy. Males must be instructed to use a latex condom during any 
sexual contact with a woman of child bearing potential (even if they have 
had a vasectomy), because it is unknown if lenalidomide is present in 
semen. 
 
15.194 Patents may experience pruritus, rash and dry skin. Because of the rare 
risk of Steven’s Johnson Syndrome, patients should immediately report 
any rash to their provider. 
 
15.195 Drug may cause hyperglycemia. Patients with diabetes or impaired 
fasting glucose may need to have their glucose levels monitored more 
closely. 
 
15.196 Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patient symptomatically and 
monitor for effectiveness. 
 
15.197 Patients may experience myalgias, arthralgias, and other generalized 
pain. Administer analgesics as ordered and monitor for their 
effectiveness. 
 
15.198 Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can 
be seen. Manage symptomatically and monitor for effectiveness. 
 
15.2 
AT-101 (10 mg R-(-)-gossypol acetic acid) 
 
15.21 Background: Ascenta Therapeutics, Inc. is developing AT-101 [R-(-)-gossypol 
acetic acid] for the treatment of patients with advanced cancer. AT-101 is the 
levorotatory enantiomer of racemic gossypol acetic acid. 
 
AT-101 is a small molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-
XL, Bcl-w and Mcl-1 and a potent inducer of the proapoptotic proteins Noxa and 
Puma. In vitro data have demonstrated that AT-101 binds to Bcl-2, Bcl-XL, Bcl-
w and Mcl-1 in the BH3 binding pocket of these proteins, thereby inhibiting their 
ability to interact with related, pro-apoptotic proteins, and thus promoting 
apoptosis. Transcriptional up-regulation of pro-apoptotic proteins Noxa and 
Puma contributes to the antitumor activity of AT-101. In addition, AT-101 is 
antiangiogenic and promotes the regression of tumor vasculature. AT-101 has 
been confirmed to induce apoptosis and related cellular events such as caspase 
activation and inhibition of mitochondrial function.  AT-101 exhibits broad 
activity in tumor cell lines and is more potent than either racemic gossypol or S-
(+)-gossypol in anti-proliferation assays. 
 
15.22 Formulation: Each AT-101 tablet contains 10 mg R-(-)-gossypol acetic acid and 
the following excipients: silicified microcrystalline cellulose, sodium starch 
glycolate, and stearic acid. 
 
15.23 Preparation and storage: AT-101 tablets should be stored under refrigeration, 
between 2 to 8ºC and protected from direct heat. To assure maximal stability, 
AT-101 should not be handled at ambient temperatures for more than 24 hours 
(i.e. for the purpose of delivery or dispensing). 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
15.24 Administration:  It is recommended that AT-101 be taken at least an hour (or 
more) before or after food. 
 
 
15.25 Pharmacokinetic information: 
a)   Absorption – Following administration of AT-101 in both the fed and fasted 
state, Cmax and AUC(0-8h) were approximately the same while AUC(0-
tlast) was higher in the fed state.  Based on the finding that food may 
increase AT-101 exposure, it is recommended that AT-101 be taken at least 
an hour (or more) before or after food. The Cmax increased with increasing 
dose. While the data was quite variable, the geometric mean values of the 
dose corrected Cmax were generally similar across dose groups while there 
was an apparent trend of lower values at the higher doses. This indicates 
there may be some dose limiting absorption of AT-101 at higher doses. Tmax 
was variable with a range of 0.5 to 8 hours post dose with an overall median 
value of approximately 3 hours. 
b)   Distribution - In all species tested, gossypol is widely distributed following 
oral or parenteral administration.  Various studies with gossypol show that it 
has extensive protein binding potential, perhaps on the order of 90% or 
greater, based on a study in swine; there is also some evidence for a 
difference in the protein binding potential between the individual 
enantiomers of gossypol.  The definitive assessment of in vitro protein 
binding potential for gossypol has been problematic due to logistical issues 
with standard assays.  Plasma pharmacokinetic profiles for gossypol in 
various animal species are consistent with redistribution of gossypol from 
blood into tissues, with the distribution into these tissues likely to be a 
consequence of the variable degree of protein binding for gossypol in each 
tissue. 
c)   Metabolism – The potential for AT-101 to inhibit or induce major 
cytochrome P450 isoenzymes was assessed in in vitro studies using human 
liver microsomes. These studies showed that AT-101 did not induce or 
inhibit the CYP450 enzymes at clinically relevant concentrations. 
 
Bioavailability, metabolism and mass balance studies have not been 
conducted in humans. In vitro metabolism studies in human liver microsomes 
did not indicate that AT-101 is metabolized by cytochrome P450 
isoenzymes. 
d)   Excretion – Excretion is thought to be primarily via feces, based on animal 
radioactivity studies.  Urinary excretion was less than 2-3% in rodents. 
 
 
15.26 Potential Drug Interactions:  The results of studies to date show no inhibition 
or induction of activities for any CYP isoform tested.  In induction studies, slight 
decreases in activities of CYP2B6, 3A4, CYP2C9 and UDPGT were actually 
observed, which were again considered to be a non-specific effect on these 
enzymes. Overall, data suggest negligible to minimal effects of AT-101 on 
CYP450 enzyme activities at concentrations likely to be achieved in humans. 
 
15.27 Known potential toxicities:  The most frequent adverse events associated with 
AT-101 dosing have been gastrointestinal findings such as nausea and vomiting; 
anorexia, dehydration, hypokalemia and fatigue have also been frequent. Most 
adverse events have been of low grade (Grade 1-2 on the NCI Common Toxicity 
Criteria scale), but a clinical picture of ileus/nonmechanical small bowel 


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Protocol Version Date: November 25, 2014 
obstruction has also been observed in approximately 10-15% of patients 
receiving 30 mg of AT-101 daily or daily for 21 of 28 days. Following these 
initial observations the dosing schedule of single-agent AT-101 was modified 
and the dose reduced for continuous dosing schedules over multiple cycles (from 
30 mg/day to 20 mg/day for 21/28 days). The incidence of ileus/non-mechanical 
small bowel obstruction was reduced to approximately 5%.  Please review the 
Investigator’s Brochure for more detailed information regarding ileus/non 
mechanical small bowel obstruction. 
 
15.28 Drug procurement:  AT-101 will be provided free of charge to patients by 
Ascenta Therapeutics. 
 
 
15.29 Nursing Guidelines:  
 
15.291 AT-101 should be taken on an empty stomach (at least one hour before 
or after meals).  
 
15.292 GI side effects were the most common. Nausea, vomiting, anorexia were 
the most common. Treat symptomatically and monitor for effectiveness. 
 
15.293 Monitor electrolyte levels, hypokalemia is common. 
 
15.294 Fatigue has been seen. Instruct patient on energy conserving lifestyle and 
monitor for effectiveness. 
 
15.295 Monitor bowel function. Patients getting higher and prolonged doses of 
the agent have presented with higher (10-15% vs. 5%) rates of ileus/or 
mechanical small bowel obstruction.  
 


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Protocol Version Date: November 25, 2014 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a phase I/II study of lenalidomide in combination with AT-101 in 
patients with relapsed CLL.  The phase I portion of this study is designed to determine 
the maximally tolerated dose (MTD) and toxicity profile of this combination. Following 
the MTD determination, the phase 2 portion of the study will assess the efficacy of this 
combination in patients with relapsed CLL using a one-stage design with an interim 
analysis. 
 
16.11    Primary Endpoint:  The primary endpoint of the phase I portion of this trial is to 
determine the maximum tolerated dose of this combination. For the phase II 
portion of this trial, the primary endpoint is the overall response rate. Throughout 
Section 16.0, response will be considered synonymous with “success” for the 
phase II portion of this study, unless specified otherwise. 
 
16.12    The phase I portion of this study is expected to require a minimum of 9 and a 
maximum of 24 evaluable patients.  The 6 patients treated at the MTD in the 
phase I portion will also be included in the phase II portion. A minimum of 8 and 
a maximum of 31 additional evaluable patients will be accrued at the MTD dose 
level for a minimum of 14 and a maximum of 37 evaluable patients in the phase 
II portion of this study. We anticipate accruing up to 5 additional patients (2 
phase I, 3 phase II) to account for ineligibility, cancellation, major treatment 
violation, or other reasons. Therefore, this study is expected to accrue a 
maximum of 26 patients in the phase I portion and 34 patients in the phase II 
portion for an overall maximum sample size of 60 patients. 
 
16.13    The anticipated accrual rate is 10-15 evaluable patients per year.  At this rate, it 
will likely take about 6 months to enroll, treat, and evaluate each phase I cohort.  
The phase I portion is expected to take between 18 and 30 months (but could be 
as long as 48 months).  The phase II portion of this study will accrue in the 
subsequent 3 years. The total study duration is expected to be approximately 5.5 
years, or until the last patient accrued has been observed for at least 6 months. 
 
16.2 
Phase 1: This portion of the study is designed to determine the MTD and toxicity profile 
of lenalidomide in combination with AT-101. 
 
16.21  MTD Definition: MTD is defined as the dose level below the lowest dose that 
induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of 
a maximum of 6 new patients). A total of 6 patients treated at the MTD will be 
sufficient to identify common toxicities at the MTD. For instance, those toxicities 
with an incidence of at least 25% will be observed with a probability of at least 
82% (1-(1-0.25)6). 
 
Refer to Section 7.24 for definition of dose-limiting toxicity (DLT). 
 
16.22 MTD Determination: 
 
Dose Escalation:  The phase I portion of this study will utilize a standard cohort 
of three design.   The dose levels to which patients will be assigned in sequential 
cohorts are described in Section 7.1.   The first cohort of three patients will be 


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Protocol Version Date: November 25, 2014 
treated at dose level 1.  Decisions on when and how to dose escalate are 
described below. 
 
16.221  Three patients will be treated at a given dose level combination and 
observed for at least 2 cycles from start of treatment to assess toxicity.  
 
16.222  If DLT is not seen in any of the 3 patients, 3 new patients will be accrued 
and treated at the next higher dose level. If DLT is seen in 2 or 3 of 3 
patients treated at a given dose level, then the next 3 patients will be 
treated at the next lower dose level, if only 3 patients were enrolled and 
treated at this lower dose level.  
 
16.223  If DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level. If 
DLT is seen in at least one of these additional three patients (≥2 of 6), the 
MTD will have been exceeded and further accrual will cease to this 
cohort. If dose-limiting toxicity (DLT) is not seen in any of the three 
additional patients, 3 new patients will be accrued and treated at the next 
higher dose level.  
 
16.224  After enrolling 6 patients on a specific dose level, if DLT is observed in 
at least 2 of 6 patients, then the MTD will have been exceeded and 
defined as the previous dose unless only 3 patients were treated at the 
lower dose level. In that case, 3 additional patients will be treated at this 
lower dose level such that a total of 6 patients are treated at the MTD to 
more fully assess the toxicities associated with the MTD. 
 
16.225  Dose de-escalation: If dose-limiting toxicity meets the stopping 
boundaries set by the above dose escalation algorithm at dose level 1 (for 
example, more than 1 out of 3 patients or more than 1 out of 6 patients), 
the next cohort of three patients will be entered at a dose level of -1. If 
dose level -1 meets the stopping boundaries, the next cohort of three 
patients will be entered at dose level -2.  Further dose re-escalation will 
depend on the toxicity profile observed at these dose levels, and re-
evaluation of the regimen by the study team may be done. 
 
16.226  If a patient fails to complete the first 2 cycles of therapy (one cycle of 
lenalidomide and one cycle of lenalidomide in combination with AT-
101) for reasons other than dose-limiting toxicity defined adverse events, 
the patient will be regarded as uninformative in regard to the primary 
study goal and an additional patient will be treated at the current dose 
level; however, all toxicity information will be utilized in the analysis. 
 


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Protocol Version Date: November 25, 2014 
16.227  Operating Characteristics for standard cohort of 3 design: The following 
table gives the probability of dose escalation at a single dose level as a 
function of the true probability of DLT at that level using the cohorts of 3 
design described above. 
 
True Rate 
of DLT (%) 
Probability of Dose Escalation 
10 
0.91 
20 
0.71 
30 
0.49 
40 
0.31 
50 
0.17 
 
16.23 Analysis Plans: All the relevant results pertaining to toxicity, MTD, response, 
timed endpoints and laboratory correlates will be examined in an exploratory and 
hypothesis-generating fashion. The small sample size and the heterogeneous 
patient population associated with phase I studies restricts the generalizability of 
the results. Any notable statistical result should only be viewed as preliminary 
evidence for further study in Phase II trials rather than a definitive finding in and 
of itself. 
 
16.231 Adverse Events Profile 
 
Platelets and hemoglobin will be graded according to the Grading Scale 
for Hematologic Adverse Events in CLL Studies in Appendix V. The 
number and severity of all adverse events (overall and by dose-level) will 
be tabulated and summarized in this patient population. The Grade 3+ 
adverse events will also be described and summarized in a similar 
fashion. This will provide an indication of the level of tolerance for this 
treatment combination in this patient group.  
 
16.232 Toxicity Profile 
 
 
The term toxicity is defined as adverse events that are classified as either 
possibly, probably, or definitely related to study treatment.  Platelets and 
hemoglobin will be graded according to the Grading Scale for 
Hematologic Adverse Events in CLL Studies in Appendix V.   All other 
toxicities will be evaluated via the ordinal CTC standard toxicity 
grading.  
  
 
Overall toxicity incidence as well as toxicity profiles by dose level, 
patient and tumor site will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive measures will 
form the basis of these analyses.  
 


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Protocol Version Date: November 25, 2014 
16.233 Response Profile   
 
A response is defined to be a CR, CRi, CCR, nPR, or PR noted as the 
objective status.  Response will be evaluated using all cycles of 
treatment.  All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for response.  
 
 
Responses will be summarized by simple descriptive summary statistics 
delineating complete and partial responses as well as stable and 
progressive disease in this patient population. The number of responses 
may indicate further evaluation for specific disease types in a Phase II 
setting. 
 
16.3  
Phase 2 Statistical Design: This is a Phase II study designed to assess the overall 
response rate as well as the toxicity associated with lenalidomide in combination with 
AT-101 in patients with relapsed CLL.   
 
16.31 Decision Rule:  
 
 
In a study of 44 patients, single agent Lenalidomide was given at a starting dose 
of 10 mg daily and could be escalated or de-escalated based on tolerability and 
response (Ferrajoli et al, 2008).60  The overall response rate for all patients was 
32%, where the median dose was 10 mg. 
 
Lenalidomide dose 
Response rate 
5 mg 
3/11 (27%) 
10 mg 
4/16 (25%) 
15 mg 
4/12 (33%) 
20 mg 
1/2 (50%) 
25 mg  
2/3 (67%) 
 
 
With the addition of AT-101, an overall response rate of 50% would be of 
interest.   
 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 30%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 50%.  The following one stage-design with an interim 
analysis is based on a two-stage Simon61 optimum design and uses 37 evaluable 
patients to test the null hypothesis that the true success proportion in a given 
patient population is at most 30%.   
 
16.311 Interim Analysis:  Enter 14 patients into the study. If 4 or fewer 
successes are observed in the first 14 evaluable patients, we will consider 
this regimen ineffective in this patient population and terminate this 
study. If at least 5 successes are observed, we will continue accrual.  
 


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Protocol Version Date: November 25, 2014 
16.312 Final Decision Rule:  Enter an additional 23 patients into the study.  If 14 
or fewer successes are observed in the first 37 evaluable patients, we will 
consider this regimen ineffective in this patient population. If 15 or more 
successes are observed in the first 37 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
population. 
 
16.313 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process.  Analyses involving over accrued 
patients are discussed in Section 16.413. 
 
16.32 Power and Significance Level:  Assuming that the number of successes is 
binomially distributed, the significance level is .10, i.e. there is a 10% chance of 
finding the drug to be effective when it truly is not.  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) and the probability 
of stopping after the interim analysis under various success proportions can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is... 
0.30 
0.35 
0.40 
0.45 
0.50 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.10 
0.25 
0.47 
0.69 
0.85 
And the probability of stopping 
after the interim analysis is … 
0.58 
0.42 
0.28 
0.17 
0.09 
 
16.33 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
 
16.4 
Phase 2 Analysis Plan:   The analysis for this trial will commence at planned time points 
(see Section 16.3) and at the time the patients have become evaluable for the primary 
endpoint. Such a decision will be made by the Statistician and Study Chair, in accord 
with CCS Standard Operating Procedures, availability of data for secondary endpoints, 
and the level of data maturity. It is anticipated that the earliest date in which the results 
will be made available via manuscript, abstract, or presentation format is when the last 
patient registered has been followed for at least 6 months. 
 
16.41 Primary Endpoint:   
 
16.411  Definition: For the phase II portion of this trial, the primary endpoint is 
the overall response rate. A response is defined to be a CR, CRi, CCR, 
nPR, or PR noted as the objective status.  The analysis will include all 
patients meeting eligibility criteria who signed a consent form and have 
begun treatment.  
 


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Protocol Version Date: November 25, 2014 
16.412  Estimation:  The proportion of successes will be estimated by the number 
of successes divided by the total number of evaluable patients.  
Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner.62 
 
16.413 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
point estimates and confidence intervals 
  
16.42 Definitions and Analyses of Secondary Endpoint: 
 
 
16.421  Overall response rate at 6 and 12 months:  The proportion of responses 
by 6 months will be estimated by the number of patients who achieve a 
response by 6 months divided by the total number of evaluable patients.  
The proportion of responses by 12 months will be estimated in a similar 
manner.  Exact binomial 95% confidence intervals for the true success 
proportions will be calculated. 
 
16.422 Time to Progression:  Time to disease progression is defined as the time 
from registration to the earliest date of documentation of disease 
progression.  If a patient dies without a documentation of disease 
progression the patient will be considered to have had tumor progression 
at the time of their death unless there is sufficient documented evidence 
to conclude no progression occurred prior to death. In the case of a 
patient starting treatment and then never returning for any evaluations, 
the patient will be censored for progression on day 1 post-registration.  
Patients who receive subsequent treatment for CLL before disease 
progression will be censored on the date of their last disease assessment 
prior to initiation of the subsequent treatment.  The distribution of time to 
progression will be estimated using the method of Kaplan-Meier 
(Kaplan-Meier, 1958).63 
 
16.423 Adverse Events:  Platelets and hemoglobin will be graded according to 
the Grading Scale for Hematologic Adverse Events in CLL Studies in 
Appendix V. The maximum grade for each type of adverse event, 
regardless of causality, will be recorded and reported for each patient, 
and frequency tables will be reviewed to determine adverse event 
patterns.  Adverse events will continue to be recorded and reported up to 
30 days after the last day of study drug treatment. 
 
16.43  Correlative Analyses:  Due to the small overall sample size, the results of the 
following analyses will be considered exploratory and hypothesis-generating in 
nature. 
 
16.431  Immune cellular microenvironment:   To determine the effect of 
lenalidomide on the immune effector arm, immune function will be 
evaluated before and during treatment by assessing T and NK cell 
quantification in both peripheral blood and bone marrow.  Changes in 
these values over time will be both graphically and quantitatively 
summarized and explored. In addition, these values will be explored in 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
relation to response (responder vs non-responder as well as by quality of 
response, i.e. CR vs PR). 
 
16.432  Effect of lenalidomide and AT-101 on molecular targets:   Specific 
molecular targets including MCl-1, Akt, Erk1/2, Bcl-2, Bcl-xl, Puma, 
Noxa and XIP will be evaluated on peripheral blood by western blot 
analysis before and during treatment.  Changes in these values over time 
will be both graphically and quantitatively summarized and explored. In 
addition, peripheral blood samples will be collected for gene expression 
profiling using microarray gene chip technology.  These samples will be 
analyzed at Mayo Clinic in Florida’s genomic core facility.  
 
16.5 
Data & Safety Monitoring 
 
16.51 The principle investigator(s) and the study statistician will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office. 
 
16.52 Adverse Event Stopping Rule for phase II patients: The stopping rule specified 
below is based on the knowledge available at study development.  We note that 
the rule may be adjusted in the event of either (1) the study re-opening to accrual 
or (2) at any time during the conduct of the trial and in consideration of newly 
acquired information regarding the adverse event profile of the treatments under 
investigation.  The study team may choose to suspend accrual because of 
unexpected adverse event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy 
either of the following: 
 
• 
if 5 or more patients in the first 14 treated patients experience a grade 4 or 
higher non-hematologic adverse event at least possibly related to treatment. 
 
• 
if after the first 14 patients have been treated, 30% of all patients experience 
a grade 4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related”, to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse events 
 
 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
16.6 
Inclusion of Women and Minorities 
 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
16.63 The geographical region served by MCCC has a population which includes 
approximately 3% minorities.  Based on prior MCCC studies involving 
similar disease sites, we expect about 3-5% of patients will be classified as 
minorities by race and about 40% of patients will be women. Expected 
sizes of racial by gender subsets are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
24 
35 
59 
Ethnic Category: Total of all subjects 
24 
36 
60 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
1 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
23 
35 
58 
Racial Category: Total of all subjects 
24 
36 
60 
 


MC128A 
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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or 
Central American, or other Spanish culture or origin, regardless of race. The 
term “Spanish origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the 
original peoples of North, Central, or South America, and who maintains 
tribal affiliations or community attachment. 
Asian – a person having origins in any of the original peoples of the Far 
East, Southeast Asia, or the Indian subcontinent including, for example, 
Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine 
Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine 
Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American – a person having origins in any of the black 
racial groups of Africa. Terms such as “Haitian” or “Negro” can be used in 
addition to “Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any 
of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the 
Middle East, or North Africa. 
 
 
 
 
 
 


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MCCC Addendum 1 
 
Protocol Version Date: November 25, 2014 
17.0  
Pathology Considerations/Tissue Biospecimens   
 
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, 
Slides, Core, 
etc. (# of 
each to 
submit) 
Visit 1:Baseline 
Visit 2: Within 24 hours of tumor 
flare 
Visit 3: 48-72 hours after start of 
tumor flare 
Visit 4: 7-10 days after start of 
tumor flare 
Visit 5: At resolution of tumor 
flare 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
 
Tumor Flare Reaction 
Optional 
Lymph 
node 
aspirate or 
biopsy 
2-3 cores 
X 
Yes 
Tissue to be 
transferred to 
pathology and 
parafin 
embeded 
block will be 
prepared 




 
66 
MCCC Addendum 1 
 
 
Protocol Version Date: November 25, 2014 
18.0 
Records and Data Collection Procedures   
 
 
18.1   Submission Timetable 
  
Initial Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study Form 
≤2 weeks after registration 
Baseline Adverse Event Form 
Pretreatment Measurement Form 
Baseline Research Blood Submission Form 
(see Section 14.0) 
Baseline Research Lymph Node 
Aspirate/Biopsy Submission Form (see 
Section 17.0) 
Baseline Research Bone Marrow Aspirate 
Submission Form 
Bone Marrow Biopsy Form 
FISH Results Form – Baseline  
Quantitative Flow Cytometry Form 
Immunophenotyping Reports including 
CD38, and ZAP-701, 2 
IgVH Mutation Analysis Report1 
Other Lab Results Form 
CLL FISH Report1 
Bone Marrow Biopsy Report1 
CT Scan Report1 
B-cell Gene Rearrangement Report1 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
1. Submit copy of the report, Attention: QAS for MC128A, Fax 
. 
2. For patients who previously had full flow immunophenotyping performed and at pre-study workup 
had limited repeat flow immunophenotyping, submit a copy of both reports. 
 


 
67 
MCCC Addendum 1 
 
 
Protocol Version Date: November 25, 2014 
  
Test Schedule Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of 
treatment 
 
Observation 
 
Evaluation/Treatment Form 
X2 
X 
 
Evaluation/Observation Form 
 
 
X1 
Nadir/Adverse Event Form 
X 
X 
X 
Measurement Form 
X 
X 
X 
Quantitative Flow Cytometry Form 
X4 
 
 
Research Blood Submission Form 
X4 (see Section 14.0) 
 
 
Research Lymph Node Aspirate/Biopsy 
Submission Form (for patients with tumor 
flare only)  
X4 (see Section 17.0) 
 
 
Research Bone Marrow Aspirate Submission 
Form 
X4 (see Section 14.0) 
X 
 
Bone Marrow Biopsy Form 
X4 
X4 
X4 
Other Lab Results Form 
X 
X 
X 
Immunophenotyping Report3 
X4 
X4 
 
B-cell Gene Rearrangement Report3 
X4 
X4 
 
Bone Marrow Biopsy Report3 
X4 
X4 
 
CT Scan Report3 
X4 
X4 
 
End of Active Treatment/Cancel Notification 
Form 
 
X 
 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
1. Complete at each evaluation during Observation (see Section 4.0). 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
3. Submit copy of the report, Attention: QAS for MC128A, Fax 
. 
4. Complete when required per the test schedule. 
 


 
68 
MCCC Addendum 1 
 
 
Protocol Version Date: November 25, 2014 
Follow-up Material(s)  
 
CRF 
Event Monitoring Phase1 
 
q. 3 months until 
PD or subsequent 
treatment for 
CLL2 
 
 
 
At PD or 
subsequent 
treatment 
for CLL2 
q. 6 mos. 
after PD or 
subsequent 
treatment 
for CLL 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. Submit copy of documentation of response or progression to the Operations Office, Attention: QAS 
for MC128A, Fax 
. 
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care and lenalidomide. 
 
19.2 
Tests to be research funded: Correlative studies described in Section 14.0 and 17.0.  The 
study drug (AT-101) will be provided free of charge to the patient. 
 
20.0 
References 
 
1. Aksentijevich I, Flinn IW: Chronic lymphocytic leukemia: advances in biology and 
therapeutics. Curr Opin Oncol 15:16-22, 2003 
2. Dighiero G, Binet JL: When and how to treat chronic lymphocytic leukemia. N Engl J 
Med 343:1799-801, 2000 
3. Keating M: Improving the complete remission rate in chronic lymphocytic leukemia. 
Am J Hematol:262-9, 1999 
4. Cheson B, Bennett J, Grever M, et al: National Cancer Institute-sponsored Working 
Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis 
and treatment. Blood 87:4990-4997, 1996 
5. Keating MJ: Chronic lymphocytic leukemia. Semin Oncol 26:107-14, 1999 
6. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil 
as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-7, 
2000 
7. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the 
randomized trials.  CLL Trialists' Collaborative Group. J Natl Cancer Institute 
91:861-8, 1999 
8. Schmitt B, Wendtner CM, Bergmann M, et al: Fludarabine combination therapy for 
the treatment of chronic lymphocytic leukemia. Clin Lymphoma 3:26-35, 2002 
9. Leporrier M, Chevret S, Cazin B, et al: Randomized comparison of fludarabine, CAP, 
and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia 
patients. Blood 98:2319-25, 2001 
10. Plunkett W, Gandhi V, Huang P, et al: Fludarabine: pharmacokinetics, mechanisms 
of action, and rationales for combination therapies. Semin Oncol 20:2-12, 1993 


 
69 
MCCC Addendum 1 
 
 
Protocol Version Date: November 25, 2014 
11. Weiss MA, Maslak PG, Jurcic JG, et al: Pentostatin and cyclophosphamide: an 
effective new regimen in previously treated patients with chronic lymphocytic 
leukemia. J Clin Oncol 21:1278-84, 2003 
12. Keating MJ, O'Brien S, Lerner S, et al: Long-term follow-up of patients with chronic 
lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 
92:1165-71, 1998 
13. Koehl U LL, Nowak B, et al.: Fludarabine and cyclophosphamide: synergistic 
cytoxicity associated with inhibition of interstrand cross-link removal. Proc Am Assn 
Cancer Res 38:2, 1997 
14. O'Brien SM, Kantarjian HM, Cortes J, et al: Results of the fludarabine and 
cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin 
Oncol 19:1414-20, 2001 
15. Marotta G, Bigazzi C, Lenoci M, et al: Low-dose fludarabine and cyclophosphamide 
in elderly patients with B-cell chronic lymphocytic leukemia refractory to 
conventional therapy. Haematologica 85:1268-70, 2000 
16. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 
monoclonal antibody therapy for relapsed indolent lymphoma: half of patients 
respond to a four-dose treatment program. J Clin Oncol 16:2825-33., 1998 
17. Piro LD, White CA, Grillo-Lopez AJ, et al: Extended Rituximab (anti-CD20 
monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-
Hodgkin's lymphoma. Ann Oncol 10:655-61., 1999 
18. Czuczman MS, Fallon A, Mohr A, et al: Rituximab in combination with CHOP or 
fludarabine in low-grade lymphoma. Semin Oncol 29:36-40. 
hDBfor=art&artType=abs&id=asonc02901c0036&target=, 2002 
19. Byrd JC, Murphy T, Howard RS, et al: Rituximab Using A Thrice Weekly Dosing 
Schedule in B-Cell Chronic Lymphocytic Leukemia and Small Lymphocytic 
Lymphoma Demonstrates Clinical Activity and Acceptable Toxicity. J Clin Oncol 
19:2153-2164, 2001 
20. O'Brien SM, Kantarjian H, Thomas DA, et al: Rituximab Dose-Escalation Trial in 
Chronic Lymphocytic Leukemia. J Clin Oncol 19:2165-2170, 2001 
21. Bellosillo B, Villamor N, Lopez-Guillermo A, et al: Complement-mediated cell death 
induced by rituximab in B-cell lymphoproliferative disorders is mediated in vitro by a 
caspase-independent mechanism involving the generation of reactive oxygen species. 
Blood 98:2771-7, 2001 
22. Golay J, Lazzari M, Facchinetti V, et al: CD20 levels determine the in vitro 
susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: 
further regulation by CD55 and CD59. Blood 98:3383-9, 2001 
23. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase 2 study of fludarabine 
with concurrent versus sequential treatment with rituximab in symptomatic, untreated 
patients with B-cell chronic lymphocytic leukemia: results from Cancer and 
Leukemia Group B 9712 (CALGB 9712). Blood 101:6-14, 2003 
24. Byrd JC PB, Park K: Rituximab added to fludarabine improves response in 
previously untreated chronic lymphocytic leukemia: Preliminary reesult from 
CALGB 9712. Proc Am Soc Clin Oncol 20:280a (Abstract 1116), 2001 
25. Hainsworth JD, Litchy S, Barton JH, et al: Single-agent rituximab as first-line and 
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Network. J Clin Oncol 21:1746-51, 2003 
26. Huhn D, von Schilling C, Wilhelm M, et al: Rituximab therapy of patients with B-cell 
chronic lymphocytic leukemia. Blood 98:1326-31, 2001 
27. Marotta G, Lenoci M, Fabbri A, et al: Efficacy of rituximab in the treatment of 
refractory chronic lymphocytic leukemia patient with bone marrow aplasia. Hematol 
J 3:299-301, 2002 
28. Garcia-Manero G, S. OB, Cortes J: Combination fludarabine, cyclophosphamide and 
rituximab for previously treated patients with chronic lymphocytic  leukemia. Blood 
96:757a, 2000 
29. Castejon R VJ, Romero Y, Briz M, Munoz RM, Durantez A.: Modulation of 
apoptosis by cytokines in B-cell chronic lymphocytic leukemia. Cytometry 38:224-
30., 1999 
30. Mainou-Fowler T PA: Modulation of apoptosis with cytokines in B-cell chronic 
lymphocytic leukaemia. Leuk Lymphoma. 21:369-77, 1996 
31. Duensing S AJ: Increased intracellular and plasma levels of basic fibroblast growth 
factor in B-cell chronic lymphocytic leukemia. Blood 85:1978-80, 1995 
32. Menzel T RZ, Calleja E, et al.: Elevated intracellular level of basic fibroblast growth 
factor correlates with stage of chronic lymphocytic leukemia and is associated with 
resistance to fludarabine. Blood 87:1056-63, 1996 
33. Konig A MT, Lynen S, et al.: Basic fibroblast growth factor (bFGF) upregulates the 
expression of bcl- 2 in B cell chronic lymphocytic leukemia cell lines resulting in 
delaying apoptosis. Leukemia 11:258-65, 1997 
34. Letai A: BH3 domains as BCL-2 inhibitors: prototype cancer therapeutics. Expert 
Opin Biol Ther 3:293-304, 2003 
35. Hanada M, Delia D, Aiello A, et al: bcl-2 gene hypomethylation and high-level 
expression in B-cell chronic lymphocytic leukemia. Blood 82:1820-8, 1993 
36. Aviram A, Rabizadeh E, Zimra Y, et al: Expression of bcl-2 and bax in cells isolated 
from B-chronic lymphocytic leukemia patients at different stages of the disease. Eur J 
Haematol 64:80-4, 2000 
37. Consoli U, Santonocito A, Stagno F, et al: Multidrug resistance mechanisms in 
chronic lymphocytic leukaemia. Br J Haematol 116:774-80, 2002 
38. Robertson LE, Plunkett W, McConnell K, et al: Bcl-2 expression in chronic 
lymphocytic leukemia and its correlation with the induction of apoptosis and clinical 
outcome. Leukemia 10:456-9, 1996 
39. Pepper C, Bentley P, Hoy T: Regulation of clinical chemoresistance by bcl-2 and bax 
oncoproteins in B-cell chronic lymphocytic leukaemia. Br J Haematol 95:513-7, 1996 
40. Pepper C, Hoy T, Bentley DP: Bcl-2/Bax ratios in chronic lymphocytic leukaemia 
and their correlation with in vitro apoptosis and clinical resistance. Br J Cancer 
76:935-8, 1997 
41. Thomas A, Pepper C, Hoy T, et al: Bcl-2 and bax expression and chlorambucil-
induced apoptosis in the T-cells and leukaemic B-cells of untreated B-cell chronic 
lymphocytic leukaemia patients. Leuk Res 24:813-21, 2000 
42. Bellosillo B, Villamor N, Lopez-Guillermo A, et al: Spontaneous and drug-induced 
apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic 
lymphocytic leukemia. Blood 100:1810-6, 2002 


 
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43. Dewson G, Snowden RT, Almond JB, et al: Conformational change and 
mitochondrial translocation of Bax accompany proteasome inhibitor-induced 
apoptosis of chronic lymphocytic leukemic cells. Oncogene 22:2643-54, 2003 
44. Starczynski J, Pepper C, Pratt G, et al: Common polymorphism G(-248)A in the 
promoter region of the bax gene results in significantly shorter survival in patients 
with chronic lymphocytic Leukemia once treatment is initiated. J Clin Oncol 
23:1514-21, 2005 
45. Kitada S, Monosov E, Chandler S, et al: Pro-apoptotic effects on CLL (chronic 
lymphocytic leukemia) or ABT-737, a novel fully synthetic Bcl-2/Bcl-XL antagonist. 
Blood, 2004 
46. Pepper C, Hooper K, Thomas A, et al: Bcl-2 antisense oligonucleotides enhance the 
cytotoxicity of chlorambucil in B-cell chronic lymphocytic leukaemia cells. Leuk 
Lymphoma 42:491-8, 2001 
47. Pepper C, Thomas A, Hoy T, et al: Antisense oligonucleotides complementary to Bax 
transcripts reduce the susceptibility of B-cell chronic lymphocytic leukaemia cells to 
apoptosis in a bcl-2 independent manner. Leuk Lymphoma 43:2003-9, 2002 
48. Rai K, Moore J, Boyd T, et al: Phase 3 randomized trial of 
fludarabine/cyclosphosphamide chemotheray with or without oblimersen sodium 
(Bcl-2 antisense; Genasense; G3139) for patients with relapsed or refractory chronic 
lymphocytic leukemia (CLL). Blood, 2004 
49. Kitada S, Andersen J, Akar S, et al: Expression of apoptosis-regulating proteins in 
chronic lymphocytic leukemia: correlations with In vitro and In vivo 
chemoresponses. Blood 91:3379-89, 1998 
50. Bannerji R, Kitada S, Flinn IW, et al: Apoptotic-regulatory and complement-
protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo 
rituximab resistance. J Clin Oncol 21:1466-71, 2003 
51. Saxena A, Viswanathan S, Moshynska O, et al: Mcl-1 and Bcl-2/Bax ratio are 
associated with treatment response but not with Rai stage in B-cell chronic 
lymphocytic leukemia. Am J Hematol 75:22-33, 2004 
52. Qian S, Hu J, Ho J, et al: The first clinical trial of gossypol on male antifertility., Clin 
Pharmacol Ther, 1980, pp 489-492 
53. Liu Z, Ziu G, Hei L, et al: Clinical trial of gollyppol as a male antifertility agent.  
Recent advances in fertility regulation. Atar:160-163, 1981 
54. Stein RC, Joseph AE, Matlin SA, et al: A preliminary clinical study of gossypol in 
advanced human cancer. Cancer Chemother Pharmacol 30:480-2, 1992 
55. Flack MR, Pyle RG, Mullen NM, et al: Oral gossypol in the treatment of metastatic 
adrenal cancer. J Clin Endocrinol Metab 76:1019-24, 1993 
56. Van Poznak C, Seidman AD, Reidenberg MM, et al: Oral gossypol in the treatment 
of patients with refractory metastatic breast cancer: a phase I/II clinical trial. Breast 
Cancer Res Treat 66:239-48, 2001 
57. Bushunow P, Reidenberg MM, Wasenko J, et al: Gossypol treatment of recurrent 
adult malignant gliomas. J Neurooncol 43:79-86, 1999 
58. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and 
response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann 
Intern Med 110:236-8, 1989 


 
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59. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood. 2008;111:5446-5456. 
60. Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl 
S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial 
remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 
2008 Jun 1;111(11):5291-7. Epub 2008 Mar 11. PubMed PMID: 18334676. 
61. Simon R: Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 
10:1-10, 1989. 
62. Duffy D, Santner T: Confidence intervals for a binomial parameter based on multistage tests. 
Biometrics 43:81- 93, 1987. 
63. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 
53:457-481, 1958. 
 
 
 
  
 
 


 
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Appendix I 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
 


 
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Appendix II 
Rai Staging System for CLL 
 
 
Modified 3-stage System 
Rai Stage 
Clinical Features 
Low Risk 
0 
Lymphocytes (L) in blood 
> 5000/mm3 and marrow > 30% only 
 
 
Intermediate Risk 
I 
L+ enlarged lymph nodes (LN) 
 
II 
L + spleen and/or liver (LN + or -) 
High Risk 
III 
L + anemia (Hbg < 11 gm/dl) 
 
IV 
L + Thrombocytopenia < 100,000/µl. 
 
Subjects in the intermediate risk group must have evidence of active disease as demonstrated by at least 
one of the following criteria: 
 
Massive or progressive splenomegaly and/or lymphadenopathy; (Massive splenomegaly is here defined 
by spleen tip > 6 cm below costal margin.) 
 
Presence of weight loss > 10% over the preceding 6 month period; 
 
Grade 2 or 3 fatigue; 
 
Fevers > 100.5°F or night sweats for greater than 2 weeks without evidence of infection; 
 
Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling 
time of less than 6 months; 
 
Worsening anemia or thrombocytopenia. 
 


 
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Appendix III 
Criteria for Diagnosis of Disease 
 
Specific diagnosis of B-Cell CLL meeting the following criteria at any time during the course of disease 
(i.e., at initial diagnosis, at relapse, etc.): 
 
• 
An absolute lymphocytosis of > 5,000/mm3. 
 
• 
Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes by manual 
differential. 
 
• 
The aspirate smear must show > 30% of nucleated cells to be lymphoid or the bone marrow core 
biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL. The overall 
cellularity must be normocellular or hypercellular. 
 
• 
Local institution lymphocyte immunophenotype must reveal a predominant B-cell monoclonal 
population sharing a B-cell marker (CD19, CD20, CD23, CD24) with the CD5 antigen, in the 
absence of other pan-T-cell markers. While the absence of CD23 expression will not exclude 
subjects, it should prompt close re-examination of the lymphocyte morphology to exclude the 
diagnosis of mantle cell lymphoma in the leukemic phase. 
 


 
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Appendix IV 
Definition of Symptomatic B-Cell 
Active disease should be clearly documented for protocol therapy. At least one of the following 
criteria should be met:  
1. Evidence of progressive marrow failure as manifested by the development of, or 
worsening of, anemia (Hgb < 11.0 g/dL) and/or thrombocytopenia (Platelets < 100 x 109) 
2. Massive (ie, at least 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly  
3. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy  
4. Progressive lymphocytosis with an increase of more than 50% over a 2-month period or 
lymphocyte doubling time (LDT) of less than 6 months. LDT can be obtained by linear 
regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks 
over an observation period of 2 to 3 months. In patients with initial blood lymphocyte 
counts of less than 30 x 109/L (30 000/µL), LDT should not be used as a single parameter 
to define a treatment indication. In addition, factors contributing to lymphocytosis or 
lymphadenopathy other than CLL (eg, infections) should be excluded.  
5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids 
or other standard therapy.  
6. Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs:  
a. Unintentional weight loss of 10% or more within the previous 6 months;  
b. significant fatigue (ie, inability to work or perform usual activities);  
c. fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence 
of infection; or  
d. night sweats for more than 1 month without evidence of infection.  


 
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Appendix V 
Grading Scale for Hematologic Toxicity in CLL Studies 
Non Hematologic Toxicity will be scored using NCI CTCAE (version 4.0) for toxicity and adverse event 
reporting.   
Hematologic toxicity will be assessed using IWCLL/Hallek December 2008 
 
Grading scale for hematologic toxicity in CLL studies  
Grade* 
 Decrease in platelets  or Hb  (nadir) from pretreatment 
value, %  
 Absolute neutrophil count/µL  
(nadir)  
0  
 No change to 10%  
  2000  
1  
 11%-24%  
  1500 and < 2000  
2  
 25%-49%  
  1000 and < 1500  
3  
 50%-74%  
  500 and < 1000  
4  
  75%  
 < 500  
* Grades: 1, mild; 2, moderate; 3, severe; 4, life-threatening; 5, fatal. Death occurring as a result of 
toxicity at any level of decrease from pretreatment will be recorded as grade 5.  
Platelet counts must be below normal levels for grades 1 to 4. If, at any level of decrease, the platelet 
count is < 20 x 109/L (20 000/µL), this will be considered grade 4 toxicity, unless a severe or life-
threatening decrease in the initial platelet count (eg, 20 x 109/L [20 000/µL]) was present pretreatment, in 
which case the patient is not evaluable for toxicity referable to platelet counts.  
Hb levels must be below normal levels for grades 1 to 4. Baseline and subsequent Hb determinations 
must be performed before any given transfusions. The use of erythropoietin is irrelevant for the grading of 
toxicity but should be documented.  
If the absolute neutrophil count (ANC) reaches < 1 x 109/L (1000/µL), it should be judged to be grade 3 
toxicity. Other decreases in the white blood cell count, or in circulating neutrophils, are not to be 
considered because a decrease in the white blood cell count is a desired therapeutic endpoint. A gradual 
decrease in granulocytes is not a reliable index in CLL for stepwise grading of toxicity. If the ANC was < 
1 x 109/L (1000/µL) before therapy, the patient is not evaluable for toxicity referable to the ANC. The use 
of growth factors such as G-CSF is not relevant to the grading of toxicity, but should be documented. 


 
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APPENDIX VI 
Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods 
Risks Associated with Pregnancy 
The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect 
of the lenalidomide on human eggs and sperm.  The risks to a fetus are not known.  However, because 
lenalidomide is related to thalidomide, and thalidomide is known to cause severe birth defects, the 
following requirements must be observed. 
Females of childbearing potential (FCBP)† must agree to use two reliable forms of contraception 
simultaneously or to practice complete abstinence from heterosexual intercourse during the following 
time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating 
in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable 
contraception must include one highly effective method (i.e. intrauterine device (IUD), hormonal [birth 
control pills, injections, or implants], tubal ligation, partner’s vasectomy) and one additional effective 
(barrier) method (i.e. latex condom, diaphragm, cervical cap).  FCBP must be referred to a qualified 
provider of contraceptive methods if needed.   
Before starting study drug:   
Female Subjects:   
• 
FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to starting 
study drug.  The first pregnancy test must be performed within 10-14 days prior to the start of 
study drug and the second pregnancy test must be performed within 24 hours prior to the start of 
study drug.  The subject may not receive study drug until the Investigator has verified that the 
results of these pregnancy tests are negative. 
• 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure, and the Appendix: Education and Counseling 
Checklist must be completed by a certified RevAssist Counselor. 
• 
Must agree to abstain from donating blood during study participation and for at least 28 days after 
discontinuation from the study. 
Male Subjects:   
• 
Must agree to use a latex condom during sexual contact with females of childbearing potential 
while participating in the study and for at least 28 days following discontinuation from the study 
even if he has undergone a successful vasectomy.  
• 
Will be warned that sharing study drug is prohibited and will be counseled about pregnancy 
precautions and potential risks of fetal exposure, and the Appendix: Education and Counseling 
Checklist must be completed by a certified RevAssist Counselor. 
• 
Must agree to abstain from donating blood, semen, or sperm during study participation and for at 
least 28 days after discontinuation from the study. 
During study participation and for 28 days following discontinuation from the study: 
All Subjects: 
• 
Only enough lenalidomide for one cycle of therapy may be dispensed with each cycle of therapy.  
• 
If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a male 
study subject during study participation, lenalidomide must be immediately discontinued. 
Female Subjects:   
• 
FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 
28 days of study participation and then every 28 days while on study, at study discontinuation, 
and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the 
                                                          
 
† A female of childbearing potential is a sexually mature woman 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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pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, 
at study discontinuation, and at days 14 and 28 following discontinuation from the study.   
• 
In addition to the required pregnancy testing, the Investigator must confirm with FCBP that she is 
continuing to use two reliable methods of birth control at each visit.   
• 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not 
share study drug and to not donate blood, and the Appendix: Education and Counseling Checklist 
must be completed by a certified RevAssist Counselor. 
• 
Pregnancy testing and counseling must be performed if a subject misses her period or if her 
pregnancy test or her menstrual bleeding is abnormal.  Study drug treatment must be discontinued 
during this evaluation. 
• 
Females must agree to abstain from breastfeeding during study participation and for at least 28 
days after discontinuation from the study. 
Male Subjects: 
• 
Counseling about the requirement for latex condom use during sexual contact with females of 
childbearing potential and the potential risks of fetal exposure must be conducted at a minimum 
of every 28 days. During counseling, subjects must be reminded to not share study drug and to 
not donate blood, sperm, or semen, and the Appendix: Education and Counseling Checklist must 
be completed by a certified RevAssist Counselor. 


 
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Appendix VII 
Education and Counseling Checklist 
 
Do Not Dispense lenalidomide (Revlimid®) if: 
• 
The patient is pregnant. 
• 
A female of childbearing potential states pregnancy tests were not conducted. 
• 
The patient states they did not use recommended effective birth control (unless practicing 
continuous abstinence. 
 
Checklist for females of childbearing potential 
I verified that pregnancy tests were performed and were negative 
 
I counseled adults and children on: 
 
• 
Potential fetal harm 
 
• 
Using 2 forms of effective birth control at the same time or abstaining from heterosexual 
intercourse 
 
• 
Continuation of 2 forms of birth control if therapy is interrupted and for 4 weeks after therapy is 
discontinued  
• 
FCBP with regular or no menstrual cycles must have pregnancy tests weekly for the first 28 days 
of study participation and then every 28 days while on study, at study discontinuation, and at day 
28 following discontinuation from the study.  If menstrual cycles are irregular, the pregnancy 
testing must occur weekly for the first 28 days and then every 14 days while on study, at study 
discontinuation, and at days 14 and 28 following discontinuation from the study.   
• 
The need to stop taking lenalidomide right away in the event of becoming pregnant and to call 
their healthcare provider immediately. Female partners of males taking lenalidomide must call 
their healthcare provider right away if they get pregnant 
 
• 
Possible side effects due to neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary 
embolism 
 
• 
Not sharing medication 
 
• 
Not donating blood while taking lenalidomide and for 4 weeks after stopping lenalidomide 
 
• 
Not to break, chew, or open lenalidomide capsules 
 
• 
Provided Medication Information Sheet for Subjects Enrolled in Clinical Research Studies using 
Investigational Drug Supply 
 
 
 
 
Checklist for females NOT of childbearing potential (natural menopause for at least 24 consecutive 
months, a hysterectomy, or bilateral oophorectomy) 
 
I counseled adults and children on: 


 
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Protocol Version Date: November 25, 2014 
 
• 
Possible side effects due to neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary 
embolism 
 
• 
Not sharing medication 
 
• 
Not donating blood while taking lenalidomide and for 4 weeks after stopping lenalidomide 
 
• 
Not to break, chew, or open lenalidomide capsules 
 
• 
Provided Medication Information Sheet for Subjects Enrolled in Clinical Research Studies using 
Investigational Drug Supply 
 
Checklist for males 
 
I counseled adults and children on: 
 
• 
Potential fetal harm 
 
• 
Need for contraception wearing a latex condom when engaging in sexual intercourse with a 
female of childbearing potential 
 
• 
Possible side effects due to neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary 
embolism 
 
• 
Not sharing medication 
 
• 
Not donating blood while taking lenalidomide and for 4 weeks after stopping lenalidomide 
 
• 
Not to break, chew, or open lenalidomide capsules 
 
• 
Provided Medication Information Sheet for Subjects Enrolled in Clinical Research Studies using 
Investigational Drug Supply 
 
 
Counselor Signature:________________________________________Date:__________ 
 
 
**Keep a copy of this checklist with the prescribing/dispensing records. ** 
 
 


 
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Appendix VIII 
Lenalidomide Information Sheet 
FOR PATIENTS ENROLLED IN CLINICAL RESEARCH STUDIES 
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply, since there may be new information. This Lenalidomide Information 
Sheet does not take the place of an informed consent to participate in clinical research or talking 
to your study doctor or healthcare provider about your medical condition or your treatment.   
What is the most important information I should know about lenalidomide? 
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known thalidomide 
causes life-threatening birth defects. Lenalidomide has not been tested in pregnant 
women but may also cause birth defects. 
If you are a female who is able to become pregnant: 
• 
Do not take lenalidomide if you are pregnant or plan to become pregnant 
• 
for 28 days before starting lenalidomide 
• 
while taking lenalidomide  
• 
during dose interruptions of lenalidomide  
• 
for 28 days after stopping lenalidomide  
• 
Stop taking lenalidomide if you become pregnant during lenalidomide 
treatment 
• 
Do not breastfeed while taking lenalidomide 
• 
You must have pregnancy testing done at the following times: 
• 
within 10 – 14 days and again 24 hours prior to the first dose of 
lenalidomide  
• 
weekly for the first 28 days 
• 
every 28 days after the first month or every 14 days if you have 
irregular menstrual periods 
• 
if you miss your period or have unusual menstrual bleeding 
• 
28 days after the last dose of lenalidomide (14 and 28 days after 
the last dose if menstrual periods are irregular) 
• 
You must practice complete abstinence or use two reliable, separate forms 
of effective birth control at the same time:  
• 
for 28 days before starting lenalidomide 
• 
while taking lenalidomide 
• 
during dose interruptions of lenalidomide  
• 
and for 28 days after stopping lenalidomide 
• 
Female partners of males taking lenalidomide should be advised to call their 
own physician right away if they get pregnant.  
 
• 
Study doctors, healthcare providers and patients should report all cases of 
pregnancy to Celgene Corporation at 
. 
 
If you are a male: 
It is not known if lenalidomide passes into semen.  
• Male patients, including those who have had a vasectomy, must use a latex 
condom during sexual intercourse with a pregnant female or a female that can 
become pregnant: 
• 
While you are taking lenalidomide   


 
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Protocol Version Date: November 25, 2014 
 
• 
for 28 days after you stop taking lenalidomide   
• Male patients should not donate sperm or semen while taking lenalidomide 
and for 28 days after stopping lenalidomide.  
2.  Lenalidomide may cause a reduction in the number of white blood cells and 
platelets.  This can lead to increased risk of infection and bleeding. You may need a 
blood transfusion or certain medicines if your blood counts drop too low.  You will have 
blood tests done as part of the clinical research trial in which you are participating.  This 
is discussed in the informed consent document. 
3.  Lenalidomide may cause an increased chance for blood clots in the veins and in the 
lungs. Call your study doctor or get emergency medical care right away if you get the 
following signs or symptoms: 
• shortness of breath 
• chest pain 
• arm or leg swelling 
 
4. Lenalidomide restrictions in sharing lenalidomide and donating blood: 
 
• Do not share lenalidomide with other people 
• Do not give blood while you take lenalidomide and for 28 days after stopping 
lenalidomide  
• You will get no more than a 28-day supply of lenalidomide at one time 
 
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information. 
 
 
 


 
84 
MCCC Addendum 1 
 
 
Protocol Version Date: November 25, 2014 
Appendix IX 
MEDICATION DIARY 
 
Name ______________________ 
 
 
 
Study No. ___________ 
Mayo Clinic No. ______________ 
 
Cycle 1 
 
Please complete this diary on a daily basis. Write in the amount of the dose of Lenalidomide that you took 
in the appropriate “Day” box.  Lenalidomide capsules should be swallowed whole, and should not be 
broken, chewed or opened.  If a dose  is missed, it should be taken as soon as possible on the same day.  If 
it is missed for the entire day, it should not be made up.  If you take more than the prescribed dose of 
lenalidomide, seek emergency medical care if needed and contact study staff immediately. 
 
If the capsules are thrown up, this should be noted on your diary but you should not take another capsule 
until your next scheduled dose.   
 
On the days that you do not take any study drug, please write in “0”. If you forget to take your daily dose, 
please write in “0”, but remember to take your prescribed dose at the next regularly scheduled time. 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Lenalidomide 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Lenalidomide 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Lenalidomide 
 
 
 
 
 
 
 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call:  ______________________ 
 
__________________  
 
 
____________________________________ 
(Date)   
 
 
 
 
(Participant’s Signature) 
 
 
Area Below Only To Be Completed only by Coordinator 
 
Number of pills returned_____     
 
Study Coordinator Initials________ 
 
Date______________________ 
 
Discrepancy Yes____ No_____