Clinical trial NCT01919619
Conditions: B-Cell Non-Hodgkin Lymphoma Hematopoietic and Lymphoid Cell Neoplasm Leukemia Lymphoma Plasma Cell Myeloma T-Cell Non-Hodgkin Lymphoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-11-04; Completion date: 2024-05-03
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies the side effects of lenalidomide and ipilimumab after stem cell transplant in treating patients with hematologic or lymphoid malignancies. Biological therapies, such as lenalidomide, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Immunotherapy with monoclonal antibodies, such as ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving lenalidomide with ipilimumab may be a better treatment for hematologic or lymphoid malignancies.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety of lenalidomide in combination with ipilimumab in autologous and allogeneic stem cell transplantation.

SECONDARY OBJECTIVES:

I. Overall response rate. II. Overall survival, progression-free survival. III. Cumulative incidence of acute and chronic graft-versus-host disease (GVHD) with the competing risk of relapse in allogeneic transplant patients.

OUTLINE:

Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21 of courses 1, 3, 5 and 7. Beginning 1-3 days after the last dose of lenalidomide patients receive one dose of ipilimumab intravenously (IV) over 90 minutes of courses 2, 4, 6 and 8. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1, 3, 6, 12, 24, and 36 months.

Arms: arm 1: Patients receive lenalidomide PO QD on days 1-21 of courses 1, 3, 5 and 7. Beginning 1-3 days after the last dose of lenalidomide patients receive one dose of ipilimumab IV over 90 minutes of courses 2, 4, 6 and 8. Treatment repeats every 28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Ipilimumab intervention 2: Lenalidomide
Intervention descriptions: intervention 1: Given IV intervention 2: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
MD Anderson IND Sponsor Cover Sheet 
 
Protocol ID 
2012-0947 
Protocol Title 
A Pilot Study of Lenalidomide Alternating with Ipilimumab Post 
Allogeneic and Autologous Stem Cell Transplantation 
Protocol Phase 
Pilot 
Protocol Version 26 
Version Date 
08 August 2022 
 
Protocol PI 
Issa F. Khouri, M.D. 
Department 
Stem Cell Transplantation and Cellular Therapy 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
119181 
 
 
 
 
 
 
 


 
 
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A Pilot Study of Lenalidomide Alternating with Ipilimumab                
Post Allogeneic and Autologous Stem Cell Transplantation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 The University of Texas MD Anderson Cancer Center, Stem Cell Transplantation and Cellular Therapy Department 
2 The University of Texas MD Anderson Cancer Center, Biostatistics Department 
Institution Study Number:  2012-0947 
Financial Support:   Bristol-Myers Squibb 
IND Holder:  The University of Texas MD Anderson Cancer Center  
 
IND Number:  119181 
Principal Investigator:  Issa F. Khouri, MD 
The University of Texas MD Anderson Cancer Center  
Stem Cell Transplantation and Cellular Therapy Department 
1515 Holcombe Blvd, Unit 0432 
Houston, TX 77030 
Telephone: 713.745.0049 
Fax: 713.794.4902 
ikhouri@mdanderson.org 
 
   
Collaborators:  Amin Alousi, MD1 
Qaiser Bashir, MD1 
Roland L. Bassett, Jr., MS2 
Richard E. Champlin, MD1 
Chitra M. Hosing, MD1 
Betul Oran, MD1 
Uday R. Popat, MD1 
 
 
   
 


 
 
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Table of Contents 
 
 
1.0 
OBJECTIVES ............................................................................................................................................... 3 
2.0  
BACKGROUND ........................................................................................................................................... 3 
3.0 
ELIGIBILITY ................................................................................................................................................ 4 
4.0 
TREATMENT PLAN ..................................................................................................................................... 6 
5.0  
EVALUATION DURING STUDY .................................................................................................................. 12 
6.0  
BACKGROUND DRUG INFORMATION ...................................................................................................... 15 
7.0 
STATISTICAL CONSIDERATIONS ............................................................................................................... 15 
8.0 
REPORTING REQUIREMENTS ................................................................................................................... 19 
10.0  
REFERENCES ............................................................................................................................................ 22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Protocol Body 
 
 
1.0 
Objectives 
 
 
The primary objective of this pilot study will be to assess the safety of lenalidomide 
in combination with ipilimumab in autologous and allogeneic stem cell 
transplantation. 
 
Secondary objectives include assessing: 
1. Overall response rate 
2. Overall survival, progression-free survival 
3. Cumulative incidence of acute and chronic GVHD with the competing 
risk of relapse in allogeneic transplant patients. 
 
 
2.0  Background 
Relapse or progression of malignancy is an important cause of failure after hematopoietic 
stem cell transplantation. Adoptive immunotherapy can induce clinical responses in several 
malignancies.1 
 
Revlimid (Lenalidomide, LEN or IMiD3) is the leading compound among the 
immunomodulatory drugs or IMiDs.2  It was developed as a structural analog of 
Thalidomide, from which it differs by the addition of an amino group and the removal of one 
of the carbonyl groups from the phthaloyl ring system. Thanks to these changes, LEN 
minimizes the toxicity typical of its parental drug, while optimizing therapeutic efficacy. This 
drug is now considered an emerging compound in hematologic malignancies. 
 
The therapeutic efficacy of LEN is mainly associated with immunomodulatory, 
antiangiogenic, anti-inflammatory and, to a lesser extent, antineoplastic effects. The drug 
has indeed been shown to modulate several components of the immune system by 
restraining pro-inflammatory cytokine production, enhancing NK cell cytotoxicity and 
regulating T-cell proliferation. in vitro studies have demonstrated that LEN induces up to a 
50 000-fold decrease in TNF-a, IL-1b, IL-6, and IL-12 production by human peripheral blood 
mononuclear cells (PBMCs), whereas synthesis of IL-2 and IFN-g was found to be 
dramatically increased.2 T-cell proliferation, differentiation, and survival are primed by LEN 
via the B7-CD28 co-stimulatory pathway. Hayashi et al. have shown that incubation of 
PBMCs in the presence of LEN leads to an increase up to 1.5 times in NK cell number as 
compared to control cultures3. LEN has also been shown to significantly affect angiogenesis 
in various cancers, presumably by uncoupling angiogenesis from secretion of VEGF 
through inhibition of Gab1 and Akt phosphorylation, both proteins being recruited 
downstream of VEGFR stimulation. 
 
Inadequate co-stimulation of T cells may be one mechanism underlying failure of adoptive 
immunotherapy. Expression of CTL4 is induced upon T cells upon activation. It competes 
with co-stimulatory receptor CD28 for the B7 ligands CD80 and CD86 on antigen-presenting 
cells. Through this and other mechanisms, CTLA4 functions as an important negative 
regulator of the duration and intensity of antigen-specific T-cell responses.5  CTLA4 is an 
important mediator of peripheral self-tolerance and tolerance to tumor antigens. Ipilimumab 


 
 
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is a fully human  immunoglobulin G1 (IgG1) monoclonal antibody that antagonizes CTLA4. 
The rational for using anti-CTL4 is to un-restrain pre-existing anticancer T-cell responses (in 
this case, induced by LEN) and possibly trigger new responses. This is the reason why this 
clinical trial with Ipilimumab is so important, especially now that Ipilimumab has been 
approved by the U.S. Food and Drug Administration for the treatment of metastatic 
melanoma. The assessment of the potentiating effect of Ipilimumab on the 
immunomodulatory effects of LEN will open new treatment options for lymphoid and other 
hematologic malignancies. 
 
Three published studies have established the safety of ipilimumab after allogeneic stem cell  
transplantation.5-7  The dose of 3.0 mg/kg iv every 3 to 4 weeks x 4 was not associated with 
significant toxicity.5-7  We are proposing the same dose level in this pilot study. 
The use of LEN after allogeneic stem cell transplantation has also been studied 
at MD Anderson using protocol 2007-0871. No patient in that trial died of graft-
versus-host disease (GVHD) induced or related to LEN. 
 
3.0 Eligibility 
3.1 
Inclusion Criteria 
a. 
Age >/= 18 years to </= 80 years. 
b. 
Hematologic or lymphoid malignancy. 
c. 
Autologous patients can be included anytime within 6 months post-
transplant, if they had no signs of progression and meet one of the 
following criteria:8-9  
i. 
Leukemia 
ii. Lymphoma (all types of B and T cell lymphoma) 
iii. Multiple myeloma 
d. 
Allogeneic patients if: 
i. 
Patients had engrafted donor cells (i.e., > 20% donor T-cell from PB/PCR); 
and, 
ii. Patients NOT in CR after their allogeneic transplant, and off 
tacrolimus and/or mycophenolate mofetil for at least 3 to 4 
weeks with no signs of GVHD; or, 
iii. Patients had evidence of relapse after their transplant who are off 
tacrolimus and/or mycophenolate mofetil or other 
immunosuppressants for GVHD for 3 to 4 weeks with no signs of 
GVHD (Prednisone doses </= 10 mg are permitted as stated 
previously). 
e. 
No active infection. 
f. 
ANC >/= 1.5 x 10
9/L; platelets >/= 50 x 10
9/L. 
g. 
Able to adhere to the study visit schedule and other protocol requirements. 
h. 
Performance status: ECOG 2 or less or Karnofsky of at least 60. 
i. 
Cardiac EF >/= 45% by 2D-ECHO within 3 months of study entry (or 
within 1 month if received chemotherapy within the past 3 months). 
j. 
FEV1, FVC and DLCO >/= 40% within 3 months of study entry (or 
within 1 month if received chemotherapy within the past 3 months). 
k. 
Serum creatinine </= 1.6 mg/dL and creatinine clearance >/= 30 
ml/min. Creatinine clearance will be calculated using the Cockcroft-


 
 
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Gault equation: Use actual body weight if it is less than or equal to 
ideal body weight. Use ideal body weight if patient greater than ideal 
body weight, but is less than or equal to 50% over ideal body weight. 
Use adjusted body weight if patient is greater than 50% over ideal 
body weight. 
l. 
Liver function tests (unless related to Gilbert’s disease or medications) 
i. 
SGPT, SGOT less than 2x the upper limit of normal range. 
ii. Direct Bilirubin <1.6 
m. Patient or legally authorized representative able to sign informed consent. 
n. 
Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to 
study entry. 
 
3.2 
Exclusion criteria 
a. 
Immunotherapy or chemotherapy with approved or 
investigational anticancer therapeutics within 4 weeks of first 
dose. 
b. 
Patients on alemtuzumab within 6 weeks prior to consenting. 
c. 
Active congestive heart failure (NYHA Class III to IV), 
symptomatic ischemia or conduction abnormalities uncontrolled 
by conventional interventions. Myocardial infarction within 6 
months of study entry. 
d. 
Deep vein thrombosis or pulmonary embolism within 3 months of study entry. 
e. 
Pregnant or breast-feeding females. (Lactating females 
must agree not to breast-feed while taking lenalidomide). 
f. 
Acute active infection requiring intravenous antibiotics, antiviral 
(except antiviral directed at hepatitis B), or antifungal agents 
within 14 days of first dose. 
g. 
Known HIV seropositive, hepatitis C infection, and/or hepatitis B 
(except for patients with hepatitis B Sag or core antibody receiving 
and responding to antiviral therapy directed at hepatitis B: these 
patients are allowed). 
h. 
Patients with other known malignancies within the past three years except: 
i. 
Adequately treated basal or squamous cell skin cancer. 
ii. Carcinoma in situ of the cervix. 
iii. Prostate cancer with Gleason score < 6 with stable PSA over 
the past three months. 
iv. Breast cancer in situ with full surgical resection. 
i. 
Significant neuropathy (grades 3 to 4 or grade 2 pain). 
j. 
Known hypersensitivity to thalidomide, lenalidomide or ipilimumab. 
k. 
Active life-threatening autoimmune disease. 
l. 
Active GVHD or recent GVHD and still on > 10 mg prednisone (or equivalent). 
m. Prior auto-immune disease. 
 
 
 


 
 
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4.0 Treatment Plan 
Eligible patients will receive lenalidomide alternating with ipilimumab for 8 cycles. 
 
Patients who are still receiving or just finished (i.e., within 3 months) the original 
treatment plan will be re-consented to receive 4 additional cycles (i.e., 8 total 
cycles). 
 
Lenalidomide will be given daily for 21 days (Cycle 1). One dose of ipilimumab 
(Cycle 2) will be given within 1-3 days from the last day of lenalidomide, then 
followed by 4 weeks of rest. 
Repeat lenalidomide daily for 21 days (Cycle 3) followed by one dose of 
ipilimumab (Cycle 4) within 1-3 days from the last dose of lenalidomide. 
Treatment will be repeated for a total of 8 cycles. 
 
 
Creatinine Clearance 
(mL/min) 
Cycles 1, 3, 5, 7 
Cycles 2, 4, 6, 8 
Greater than 60 
Lenalidomide 10 mg PO 
daily for 21 days 
Ipilimumab 3 mg/kg IV x 1 
dose (given 1-3 days after 
lenalidomide, then followed 
by 4 weeks of rest) 
30 to 60 
Lenalidomide 5 mg PO 
daily for 21 days 
Ipilimumab 3 mg/kg IV x 1 
dose (given 1-3 days after 
the last dose of 
lenalidomide) 
 
Creatinine clearance. Use Cockcroft-Gault formula and ideal body weight (IBW) as 
described above in inclusion criteria (Section 3.1) 
 
If the starting combination of lenalidomide 10 mg/day alternating with ipilimumab 3 
mg/kg results in toxicity in the first 3 of 3 patients (as defined in toxicity monitoring 
rule) then subsequent patients will be started at a lower combination dose of 
lenalidomide 5 mg/day (or 5 mg every other day for creatinine clearance of 30 to 
60 ml/min) and ipilimumab 3 mg/kg. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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4.1 Management of Immune-Mediated toxicity from ipilimumab: 
There are no dose reductions for Ipilimumab. The only modifications to drug are to 
pause until improvement or stop. 
 
 
 


 
 
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4.2 Ipilimumab specific requirement/toxicity management 
1. Liver toxicity 
a. Monitor liver function and evaluate for signs of hepatotoxicity prior to 
each dose (cycles 2, 4, 6, and 8). If hepatotoxicity develops, liver 
function should be monitored frequently until resolution. 
2. Other monitoring 
a. Monitor serum chemistries before each dose 
b. Monitor for signs of hypophysitis, adrenal insufficiency and thyroid disorders 
i. 
Abdominal pain, fatigue, headache, hypotension, mental status 
changes, unusual bowel habits 
c. TSH, free T4 and total cortisol level should be checked at baseline, 
prior to each dose and as clinically indicated 
d. Monitor for signs or symptoms of enterocolitis 
e. Monitor for signs of motor or sensory neuropathy 
f. 
Monitor for ocular toxicity at baseline then and before each dose 
 
4.3 Lenalidomide specific requirements/toxicity management 
 
1. Females of childbearing potential (FCBP)† must have a negative serum 
or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 
– 14 days prior to and again within 24 hours of the first dose of 
lenalidomide in Cycles 1, 3, 5, and 7 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 


 
 
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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. See 
Appendix C: Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods. 
a. All study participants must be registered into the mandatory 
Revlimid REMS
TM program, and be willing and able to comply with 
the requirements of the Revlimid REMS
TM program. 
b. Prescriptions must be filled within 7 days. 
2. Dosing Regimen: Patients will be given a pill diary for Cycles 1, 3, 5, 
and 7 in order to document self-administration of the lenalidomide. 
a. The drug will be given in the morning at approximately the same time 
each day for a total of 21 days (which should be consecutive, unless 
held for toxicities as described in the table below). Only enough 
lenalidomide for 21-days of therapy will be supplied to the patient. 
b. Lenalidomide capsules should be swallowed whole, and should 
not be broken, chewed or opened. 
c. If a dose of lenalidomide 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. 
d. Patients who take more than the prescribed dose of 
lenalidomide should be instructed to seek emergency medical 
care if needed and contact study staff immediately. 
e. Subjects experiencing adverse events may need study treatment modifications 
f. Special Handling Instructions 
g. Females of childbearing potential should not handle or 
administer lenalidomide unless they are wearing gloves. 
 
 


 
 
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NCI CTC Toxicity Grade 
Action 
Grade 3 neutropenia associated with 
fever (temperature >/= 38.5° C) or Grade 
4 neutropenia  
(ANC </= 500/mm3, </= 75% of 
baseline)*. 
1) Hold (interrupt dose). 
2) Follow CBC weekly until resolution or 
stabilization 
3) If neutropenia has resolved to </= grade 2, 
implement one dose reduction and continue therapy. 
4) If neutropenia is the only toxicity for which a dose 
reduction is required, GCSF may be used and the 
lenalidomide dose maintenance. 
 
 
Thrombocytopenia Grade 4 (platelet 
count 
</= 25,000/mm3)*. 
1) Hold (interrupt dose). 
2) Follow CBC weekly until resolution or 
stabilization 
3) If thrombocytopenia resolves to </= grade 2, implement 
one dose reduction and continue therapy. 
Non-blistering rash 
Grade 3 
 
 
 
 
Grade 4 
1) If grade 3, hold (interrupt) dose. Follow weekly until 
resolution or stabilization. 
2) If the toxicity resolves to </= grade 1, implement one 
dose reduction and continue therapy. 
 
 
1) Discontinue lenalidomide study drug. 
Desquamating (blistering) rash-any 
Grade 
Discontinue lenalidomide study drug. 
Erythema multiforme 
Grade 3 
Discontinue lenalidomide study drug. 
Neuropathy 
Grade 3 
 
 
 
 
Grade 4 
1) If grade 3, hold (interrupt) dose. Follow weekly until 
resolution or stabilization. 
2) If the toxicity resolves to </= grade 2, implement one of 
dose reduction and continue therapy. 
 
 
Discontinue lenalidomide study drug. 
Sinus bradycardia/other cardiac 
arrhythmia 
Grade 2 
 
 
 
 
>/= Grade 3 
1) Hold (interrupt dose). Follow at least weekly until 
resolution or stabilization. 
2) If the toxicity resolves to </= grade 1, implement one 
dose reduction and continue therapy. 
 
 
 
Discontinue lenalidomide study drug. 
Allergic reaction or hypersensitivity 
Grade 3 
 
 
 
 
 
Grade 4 
1) Hold (interrupt dose). Follow at least weekly 
until resolution or stabilization 
2) If the toxicity resolves to </= grade 1, implement one 
dose reduction and continue therapy. 
 
 
 
Discontinue lenalidomide study drug. 


 
 
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NCI CTC Toxicity Grade 
Action 
Venous thrombosis/embolism 
>/= Grade 3 
Hold (interrupt) dose and start anticoagulation; restart at 
investigator’s discretion (maintain dose level). 
Hepatic or other non-hematologic toxicity 
assessed as lenalidomide-related 
>/= Grade 3 
1) Hold (interrupt) dose. Follow at least weekly until 
resolution or stabilization. 
2) If the toxicity resolves to </= grade 2, implement one 
dose reduction and continue therapy. 
Tumor flare refractory to oral pain meds 
and/or antihistamines 
Hold dose and differentiate tumor flare from progression. 
Restart therapy at the investigator’s discretion. 
 
4. Treatment and Dose Modification for Tumor Lysis Syndrome for 
Patients receiving Lenalidomide 
a. All subjects meeting criteria of laboratory TLS or >/= Grade 1 TLS 
according to the Cairo-Bishop Definition of Tumor Lysis Syndrome 
(see Appendix D) should receive vigorous intravenous hydration and 
should be considered for rasburicase therapy as needed to reduce 
hyperuricemia, until correction of electrolyte abnormalities. 
i. 
In cases of laboratory TLS and Grade 1 TLS (see Appendix D: 
Cairo-Bishop Definition of Tumor Lysis Syndrome), lenalidomide 
will be continued at the same dose without interruption or dose 
reduction. TLS prophylaxis measures outlined in Lenalidomide 
Maintenance should be continued or re-instituted. 
ii. Subjects with >/= Grade 2 TLS (see Appendix D: Cairo-Bishop 
Definition of Tumor Lysis Syndrome) will be managed as follows in 
addition to intravenous hydration and consideration for rasburicase 
therapy (above). 
1. Hold (interrupt) treatment. 
2. First episode: restart lenalidomide at the current dose with 
appropriate TLS prophylaxis after resolution of electrolyte 
abnormalities to Grade 0 
3. Subsequent episodes: restart lenalidomide with appropriate TLS 
prophylaxis after resolution of electrolyte abnormalities to Grade 
0. At physician discretion, the lenalidomide dose may be restarted 
at the current dose or lenalidomide may be reduced by 1 dose 
level. 
4. First or subsequent episodes: subjects should be closely 
monitored for signs of TLS after resuming treatment. To monitor for 
TLS, serum chemistry and uric acid tests should be performed at 
least every week following initiation of lenalidomide for 4 
consecutive weeks and on Day 3 or 4 following initiation of 
lenalidomide. 
 
5. Tumor Flare Reaction (TFR) 
a. Prophylaxis for TFR is not recommended for patients who receive lenalidomide. 
i. 
Grade 1 TFR may be treated with NSAIDs (i.e. ibuprofen 400-600 mg 
orally every 4-6 hours as needed). 
ii. TFR >/= Grade 2 may be treated with corticosteroids. Narcotic 
analgesics may be added as needed for pain control in subjects 
experiencing >/= Grade 2 tumor flare. 
 


 
 
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6. Recommended Concomitant Therapy 
a. Subjects should receive full supportive care, including transfusions of 
blood and blood products, antibiotics, antiemetics, antihistamines, and 
allopurinol when appropriate. 
b. Anticoagulation Consideration 
i. 
Lenalidomide increases the risk of thrombotic events in patients 
who are at high risk or with a history a thrombosis, in particular 
when combined with other drugs known to cause thrombosis. 
ii. When lenalidomide is combined with other agents such as 
steroids (e.g. dexamethasone, prednisone), 
anthracyclines (Doxil, Adriamycin) and erythropoietin the 
risk of thrombosis is increased. 
iii. For this study, patients will receive one aspirin (81 mg) a day while 
on lenalidomide. Low molecular weight heparin may be utilized in 
patients that are intolerant to aspirin. Coumadin should be used 
with caution and close monitoring of INR. 
iv. Patients who already have a history of deep-vein thrombosis or 
pulmonary embolism will receive either coumadin or low-
molecular weight heparin while on lenalidomide. 
v. If patients develop thrombosis or embolism while they are receiving 
aspirin prophylaxis, lenalidomide will be held, patients will be 
anticoagulated, and once a stable anticoagulation is achieved, 
patients with be restarted on the same dose of lenalidomide. 
Patients will then continue to receive either coumadin or 
low-molecular weight heparin as long as they continue to receive lenalidomide. 
 
7. Prohibited Concomitant Therapy 
a. Concomitant use of sargramostim (GM-CSF), other anti-cancer 
therapies, including radiation, thalidomide, or other investigational 
agents is not permitted while subjects are receiving study drug during 
the treatment phase of the study. Concomitant medications will be 
documented in the medical record but will not be entered into the case 
report form. 
 
 
5.0  Evaluation During Study 
1. Serum pregnancy test within 10 to 14 days prior to and again within 24 hours 
prior to the first dose of lenalidomide for Cycles 1, 3, 5, and 7. 
2. Baseline: 
a. Thyroid function tests (TSH and free T4) 
b. Total cortisol level 
c. Standard chemistries including AST, ALT, Direct and Indirect Bilirubin, Alk Phos, 
LDH, 
Albumin, BUN, serum creatinine, CBC 
d. For multiple myeloma patients only (within 30 days of registration): SPEP 
and serum IFE, UPEP and urine IFE, immunoglobulins IgA, IgG, IgM, 
Beta 2 microglobulin, Serum free kappa and lambda light chain assay. 
Bone marrow aspiration and biopsy. Bone survey. 
 


 
 
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3. Before Cycle 1 (if baseline tests and/or exam are > 7 days before start of Cycle 1): 
a. Standard chemistries including AST, ALT, Direct and Indirect Bilirubin, Alk Phos, 
LDH, 
Albumin, BUN, serum creatinine, CBC 
b. Physical examination and toxicity assessment 
c. Creatinine clearance. Use Cockcroft-gault formula and ideal body 
weight (IBW). Use adjusted body weight if >50% over IBW 
4. Before Cycles 3, 5, and 7: 
a. Standard chemistries including AST, ALT, Direct and Indirect Bilirubin, Alk Phos, 
LDH, 
Albumin, BUN, serum creatinine, CBC 
b. Physical examination and toxicity assessment 
c. Creatinine clearance. Use Cockcroft-gault formula and ideal body 
weight (IBW). Use adjusted body weight if >50% over IBW 
5. Day 14 (+/-2 days) in Cycles 1, 3, 5, and 7: CBC 
6. Before Cycles 2, 4, 6, and 8: 
a. Thyroid function tests (TSH and free T4) 
b. Total cortisol level 
c. Standard chemistries including AST, ALT, Direct and Indirect Bilirubin, 
Alk Phos, LDH, Albumin, BUN, serum creatinine, CBC 
d. Physical examination and toxicity assessment (and GVHD assessment in allos) 
e. Ocular exam to assess for ocular toxicity if clinically indicated. 
7. At 1 (+/- 7 days), 3 (+/- 10 days), 6 (+/- 15 days) months, and (+/- 30 days) 
for months 12, 24, and 36 after last dose of ipilimumab and/or when 
clinically indicated: 
a. Physical examination and toxicity assessment. 
b. Assessment for toxicity (through 30 days after last dose of study drug) 
c. Assessment for GVHD (in allogeneic patients) 
d. Thyroid function tests (TSH and free T4) 
e. Total cortisol level 
f. Standard chemistries including AST, ALT, Direct and Indirect Bilirubin, Alk Phos, LDH, 
Albumin, BUN, serum creatinine, CBC 
g. Bone marrow aspiration and biopsy, CT scan, PET/CT scan depending on 
patient’s type of hematologic or lymphoid malignancy 
h. For multiple myeloma patients only: SPEP and serum IFE, UPEP and urine 
IFE, immunoglobulins IgA, IgG, IgM, Beta 2 microglobulin, Serum free 
kappa and lambda light chain assay at each visit. 
Bone marrow at 1 month follow-up and as clinically indicated. 
Bone survey (+/- 30 days) for months 12, 24, and 36 after last dose of 
ipilimumab and/or when clinically indicated. 
 
8. The International Working Group Response Criteria (Appendix I.) will be used. 
9. We will use the International Myeloma Working Group (IMWG) uniform 
response criteria for multiple myeloma patients. All response categories 
require no known evidence of progressive or new bone lesions. 
 
International Myeloma Working Group uniform response criteria. 
All response categories require two consecutive assessments made at any time. 
All response categories require no known evidence of progressive or new bone lesions. 
 
 


 
 
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Stringent complete response (sCR) (all of the following): 
1. CR as defined. 
2. Normal free light chain ratio 
3. Absence of clonal cells in bone marrow by 
inmmunohistochemistry or immunofluorescence (defined by 
absence of abnormal k/l ratio of > 4:1 or <1:2) 
 
Complete response (CR) (all of the following): 
1. Negative immunofixation in serum and urine. 
2. £ 5% plasma cells in the bone marrow. 
3. Disappearance of any soft tissue plasmacytomas. 
 
Note: While healing of pre-existing bone lesions is not required, no new lytic 
lesions should appear. Further compression fracture of previously known 
spine lesion will not be considered as progressive disease. 
 
Very good partial response (VGPR) (one of the following): 
1. Serum and urine M protein detectable by immunofixation but not by electrophoresis. 
2. 90% or greater reduction in serum M protein plus urine M protein level < 100 mg per 
4h. 
 
Partial response (PR) (all of the following): 
1. Reduction by > 50% in serum monoclonal protein. 
2. Reduction of urinary monoclonal protein to < 200 mg/24h or > 90%. 
 
Stable disease: 
1. Not meeting criteria for CR, VGPR, PR or PD. 
 
Progressive disease (PD) (any one or more of the following): 
1. Increase of ³ 25% from baseline in: 
Serum M protein (absolute increase must be ³ 0.5 g/dL). 
Urine M component (absolute increase must be ³ 200 mg/24h). Only 
in patients without measurable serum and urine M protein levels. 
Difference between involved and uninvolved FLC levels (absolute increase 
must be > 10 mg/dL). 
Bone marrow plasma percentage (absolute % must be ³ 10%). 
2. Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas. 
3. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL 
or 2.65 mol/L) that can be solely attributed to the myeloma. 
 
Relapse from CR (any one or more of the following): 
1. Reappearance of serum or urine M protein by immunofixation or electrophoresis. 
2. Development ³ 5% plasma cells in the bone marrow. 
3. Appearance of any other sign of progression (i.e., new plasmacytoma, 
lytic bone lesion or hypercalcemia). 
 
 


 
 
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6.0  Background Drug Information 
See package inserts for YERVOY® (ipilimumab) in Appendix E. and REVLIMID® 
(lenalidomide) in Appendix F. 
 
7.0 Statistical Considerations 
Overview 
The primary objective of this study will be to assess the safety of lenalidomide 
alternating with ipilimumab in stem cell transplantation. Patients will receive 
lenalidomide alternating with ipilimumab for 8 cycles (lenalidomide for 21 days, 
then one dose of ipilimumab, then repeat lenalidomide 4 weeks later, etc.). The 
starting and highest allowable dose of lenalidomide in this study will be 10 mg/d. 
Dose reductions to 5 mg may be allowed within patient based on clinical practice. 
Ipilimumab is fixed at 3 mg/kg. If the starting combination of lenalidomide 10 mg/d 
and ipilimumab 3 mg/kg results in toxicity, as defined below in the toxicity 
monitoring rule, in the first 3 of 3 patients, subsequent patients will be started at a 
lower combination dose of lenalidomide 5 mg/d and ipilimumab 3 mg/kg. 
 
Secondary objectives include assessing overall response rate, overall survival, 
progression-free survival, and the cumulative incidence of acute and chronic 
GVHD with the competing risk of relapse in allogeneic transplant patients. 
 
Safety Monitoring 
We expect to accrue a total of 40 transplant patients onto two arms: Autologous 
(N=25) and allogeneic (N=15). All patients will receive lenalidomide alternating 
with ipilimumab (L+I). Each transplant arm will be monitored separately using 
monitoring rules for toxicity. The following stopping rules and boundaries were 
developed using the Multc Lean Desktop application (version 2.1.0) in the 
Biostatistics department. 
 
The Principal Investigator and assigned Research Nurse will review the enrolled 
patients monthly while on active treatment to assess adverse events and stopping 
rules. The Biostatistician will be consulted as necessary. The data monitoring plan 
will be provided by the MD Anderson IND Office. This office is responsible to 
monitor the protocol conduct and data entry. 
 
Toxicity monitoring rules: Each transplant arm (either autologous or allogeneic) 
will be monitored separately for toxicity. If there is a high probability of observing 
more than a 30% toxicity rate in either arm, that arm will be stopped. Toxicity for 
this stopping rule will include the following, at any time during active study 
treatment, which is defined as the first eight cycles plus 30 days following the last 
dose of study drug: 
· 
Any grade 4 hematological toxicity at least probably related to study drug 
that does not resolve within 2 weeks 
· 
Any immune-mediated reaction to ipilimumab that requires permanent 
cessation of the drug 


 
 
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7
· 
Any other grade 3-5 organ toxicity at least probably related to study drug 
· 
(Allogeneic arm only) Any acute grade III or higher GVHD. 
 
Bayesian sequential monitoring will be employed to perform interim safety 
monitoring targeting a toxicity rate of not more than 30%. Patients will be 
monitored in cohorts of 1. 
 
Autologous Arm 
For the autologous arm, accrual will be stopped early if 
Pr [ prob(toxicity) > 0.30 | data] > 0.975 
That is, if we determine that there is a greater than 97.5% chance that the toxicity 
rate is greater than 30% in this arm, then accrual will be stopped. We assume a 
beta (0.6, 1.4) prior distribution for the toxicity rate, which has a mean of 0.3 
corresponding to the 30% target toxicity rate. Stopping boundaries corresponding 
to this probability criterion are to terminate accrual in autologous patients if 
 
 
If there are this many 
(or more) patients in 
the autologous 
transplant arm with 
Toxicity 
Stop the arm if this 
many patients in the 
arm 
3 
3 
4 
4-5 
5 
5-7 
6 
6-9 
7 
7-11 
8 
8-13 
9 
9-16 
10 
10-18 
11 
11-21 
12 
12-23 
13 
13-24 
14 
ALWAYS STOP 
 
Patients must complete at least two cycles of treatment or have toxicity to be 
included in the rule. Patients who complete at least two cycles but drop out 
without experiencing toxicity will be included but not counted as toxicities. If 
accrual onto this arm is stopped, the study will continue enrolling patients to the 
allogeneic transplant arm. 
 
The rule will reset at lenalidomide 5 mg if the first 3 of 3 patients at the 
combination 10 mg lenalidomide dose experience toxicity. If the rule resets after 
the first three patients, we will continue to enroll up to 25 patients in the 
autologous arm at the lower combination dose using lenalidomide 5 mg. The 
Biostatistical collaborator will be consulted as necessary. 
 


 
 
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The operating characteristics of this rule are shown below. 
 
Table 1. Operating Characteristics for Toxicity Stopping Rule in Autologous Arm 
 
Achieved Sample Size Percentiles 
If the true 
toxicity rate is... 
Early 
Stopping 
Probability 
25th 
50th 
75th 
0.1 
0.0014 
25 
25 
25 
0.2 
0.0163 
25 
25 
25 
0.3 
0.0891 
25 
25 
25 
0.4 
0.3013 
18 
25 
25 
0.5 
0.6324 
7 
16 
25 
0.6 
0.8929 
5 
9 
16 
0.7 
0.9872 
3 
5 
9 
 
 
Allogeneic Arm 
For the allogeneic arm, accrual will be stopped early if 
Pr [ prob(toxicity) > 0.30 | data] > 0.95 
That is, if we determine that there is a greater than 95% chance that the toxicity 
rate is greater than 30% in this arm, then accrual for this arm will be stopped. We 
assume a beta (0.6, 1.4) prior distribution for the toxicity rate, which has a mean 
of 0.3 corresponding to the 30% target toxicity rate. Stopping boundaries 
corresponding to this probability criterion are to terminate accrual in allogeneic 
patients if 
 
If there are this many (or 
more) patients in the 
allogeneic transplant 
arm with 
Toxicity 
Stop the arm if this 
many patients in this 
arm 
3 
3-4 
4 
5-6 
5 
7-9 
6 
10-11 
7 
12-13 
8 
14-15 
9 
ALWAYS STOP 
 
Patients must complete at least two cycles of treatment or have toxicity to be 
included in the rule. Patients who complete at least two cycles but drop out 
without experiencing toxicity will be included but not counted as toxicities. If 
accrual onto this arm is stopped, the study will continue enrolling patients to 
autologous arm. 
 
The rule will reset at lenalidomide 5 mg if the first 3 of 3 patients at the 
combination 10 mg lenalidomide dose experience toxicity. If the rule resets after 


 
 
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the first three patients, we will continue to enroll up to 15 patients in the allogeneic 
arm at the lower combination dose using lenalidomide 5 mg. The Biostatistical 
collaborator will be consulted as necessary. 
 
The operating characteristics of this rule are shown below. 
 
Table 2. Operating Characteristics for Toxicity Stopping Rule in Allogeneic 
Arm 
 
Achieved Sample Size Percentiles 
If the true 
toxicity rate is... 
Early 
Stopping 
Probability 
25th 
50th 
75th 
0.1 
0.0016 
15 
15 
15 
0.2 
0.0210 
15 
15 
15 
0.3 
0.0998 
15 
15 
15 
0.4 
0.2780 
14 
15 
15 
0.5 
0.5367 
7 
12 
15 
0.6 
0.7866 
3 
7 
12 
0.7 
0.9406 
3 
5 
7 
 
Primary Objective 
We will estimate the toxicity rate in each arm along with a corresponding 95% 
credible interval. In addition, toxicity will be summarized by arm, type, and grade. 
 
Secondary Objectives 
For secondary objectives, we will estimate response at the end of eight cycles and 
overall with a 95% confidence interval. We will also estimate specific response 
types such as humoral and cellular. This data will be used to inform future studies 
using higher dose combinations. With 15 patients assigned to a transplant arm, if 
the response rate is 20%, an asymptotic 95% confidence interval will be (0, 
0.402). With 25 patients assigned to a transplant arm, if the response rate is 20%, 
an asymptotic 95% confidence interval will be (0.043, 0.357). 
Kaplan-Meier10 survival curves will be used to estimate overall survival and 
progression-free survival. We will also assess the rates of acute and chronic 
GVHD, other organ toxicity, and secondary immune-based diseases such as 
arthritis, lupus, and thyroid dysfunction. We will use the method of Gooley et al11 to 
estimate the cumulative incidence of acute and chronic GVHD with the competing 
risk of relapse in allogeneic transplant patients. Cox proportional hazards 
regression analysis will be used to model the association between overall survival 
and progression-free survival and disease and demographic covariates of interest, 
including data from the correlative cytokine, immune, and pharmacokinetic 
studies. 
 
 
 
 
 
 
 


 
 
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Summary/Cohort Reports 
The Principal Investigator is responsible for completing a safety/efficacy summary 
report, and submitting it to the IND Office Medical Affairs and Safety Group, for 
review and approval. This should be submitted after the first 3 evaluable patients 
per cohort, complete 30 days after the last dose of study treatment, and prior to 
changing dose levels; and every patient per cohort, thereafter. 
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory 
Binder under “sponsor correspondence”. 
 
 
8.0 Reporting Requirements 
8.1 Expected Adverse Events and Grading 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial 
The research team will ensure that all adverse events are entered into the study 
case report form CORe/PDMS. All adverse events entered into the case report 
form must have a verifiable source document that is maintained in the subject’s 
medical record. PDMS/CORe will be used as the electronic case report form for 
this protocol. 
 
1. All patients will be registered in CORe 
2. The severity of the adverse events (AEs) will be graded according to the 
Common Terminology Criteria v4.0 (CTCAE) 
3. For the purpose of causality: 
a. Known adverse events of lenalidomide and ipilimumab will be reported as 
definitely related. 
b. When the relationship of the adverse event cannot be ruled out with 
certainty the AE may be considered probable or possible related. 
c. Adverse events known to be related to drugs used for supportive 
treatment will be scored as unrelated. 
d. The principal investigator will be final arbiter in determining causality assessment. 
 
8.2 Adverse events considered serious 
1. 
Graft Failure/rejection. 
2. 
Any expected or unexpected event resulting in an irreversible condition 
and/or leading to death. 
 
8.3 Serious Adverse Event Reporting (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes: 
 
· 
Death 
· 
A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 


 
 
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experience that, had it occurred in a more severe form, might have caused 
death. 
· 
Inpatient hospitalization or prolongation of existing hospitalization 
· 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
· 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 
312.32). 
 
· 
Important medical events as defined above, may also be considered 
serious adverse events. Any important medical event can and should be 
reported as an SAE if deemed appropriate by the Principal Investigator 
or the IND Sponsor, IND Office. 
 
· 
All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for Investigators 
on Reporting Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working 
days of knowledge of the event). 
 
· 
All life-threatening or fatal events, that are unexpected, and related to the 
study drug, must have a written report submitted within 24 hours (next working 
day) of knowledge of the event to the Safety Project Manager in the IND 
Office. 
 
· 
Unless otherwise noted, the electronic SAE application (eSAE) will 
be utilized for safety reporting to the IND Office and MDACC IRB. 
 
· 
Serious adverse events will be captured from the time of the first 
protocol-specific intervention, until 30 days after the last dose of drug, 
unless the participant withdraws consent. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have 
returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 
· 
Additionally, any serious adverse events that occur after the 30 day 
time period that are related to the study treatment must be reported to 
the IND Office. This may include the development of a secondary 
malignancy. 
 


 
 
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Reporting to FDA: 
 
· 
Serious adverse events will be forwarded to FDA by the IND Sponsor 
(Safety Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, 
and Institutional Review Board policy. 
 
9.0 
Criteria for Removal from the Study 
9.1 Completion of study. This is defined as three years after the last dose if Ipilimumab. 
9.2 Disease progression. 
9.3 Intolerable side effects. 
9.4 Unable to follow study directions. 
9.5 Withdrawal of consent. 
 
 


 
 
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10.0  References 
 
 
1. 
Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple 
myeloma. Blood 2002;100:3063–7. 
2. 
Hayashi T, Hideshima T, Akiyama M, et al. Molecular mechanisms whereby 
immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 
5;128:192–203. 
3. 
Salomon B, Bluestone JA. Complexities of CD28/B7:CTLA-4 costimulatory pathways in 
autoimmunity and transplantation. Annu Rev Immunol 2001;19:225-52. 
4. 
Korman AJ, Peggs KS, Allison JP. Checkpoint blockade in cancer immunotherapy. Adv 
Immunol 2006;90:297-339. 
5. 
Bashey A, Medina B, Corringham S, et al. CTLA4 blockade with ipilimumab to treat 
relapse of malignancy after allogeneic hematopoietic transplantation. Blood 2009; 
113:1581-1588. 
6. 
Zhou J, Bashey A, Zhong R, et al. CTLA-$ blockade following relapse of malignancy 
after allogeneic stem cell transplantation is associated with T cell activation but not with 
increased levels of T regulatory cells. Biol Blood Marrow Transplant 2011, 17:682-690 
7. 
Davids MS, Kim HT, Costello CL, et al. A multicenter mhase I/Ib study of ipilimumab for 
relapsed hematologic malignancies after allogeneic hematopoietic stem cell 
transplantation. Blood/American Society of Hematology. 2015; 126:Abstract 860. 
8. 
Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for Patients with Relapse after 
Allogeneic Transplantation. N Engl J Med. 2016;375:143-53. 
9. 
Khouri, IF, Curbelo, IR, Turturro, F, et al. Lenalidomide alternating with ipilimumab for 
lymphoma and chronic lymphocytic leukemia after allogeneic or autologous stem cell 
transplantation. ASH abstract. 2016. 
10. Kaplan EL and Meier P. Non-parametric estimation from incomplete observations. 
Journal of the American Statistical Association. 1958;53:457-481. 
11. Gooley TA, Leisenring W, Crowley J, and Storer BE. Estimation of failure probabilities 
in the presence of competing risks: new representations of old estimators. Statistics in 
Medicine. 1999; 18:695-706.