A Phase 2 Clinical Trial of Rituxan and B-Glucan PGG in Relapsed Indolent Non-Hodgkin Lymphoma
Phase: PHASE2
Conditions: Relapsed/Refractory Indolent B Cell Non-Hodgkin Lymphomas
Sponsor: Dana-Farber Cancer Institute

Imprime PGG and rituximab for relapsed indolent NHL 
November 13, 2018 
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Protocol Version Date: Version 9: November 13, 2018 
 
NCI Protocol #: Not applicable 
IND #: 119016 
Local Protocol #: 13-398 
 
 
Title: A Phase 2 Clinical Trial of Rituximab and β-glucan PGG in Relapsed Indolent 
Non-Hodgkin Lymphoma. 
 
Principal Investigator: Caron Jacobson, MD 
 
Coordinating Center: Dana-Farber Cancer Institute 
  
Co-Investigators:  
 DFCI: Arnold Freedman, MD; Philippe Armand, MD; Ann LaCasce, MD; David 
C Fisher, MD; Matthew Davids, MD; Katherine Stephans, NP; Barbara Virchick, 
APRN;  Jennifer R. Brown, MD, PhD; Eric Jacobsen, MD 
 
Statistician: Robert Redd 
 
Study Coordinator: Not applicable 
 
Responsible Research Nurse: Not applicable 
 
Responsible Data Manager: Not applicable 
 
Agent(s):  Rituximab (NSC#; IND#) - ; Imprime PGG (NSC#; IND#) - Biothera  
 

Imprime PGG and rituximab for relapsed indolent NHL 
November 13, 2018 
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SCHEMA 
Definitions 
 
 
   Treatment               Response        Follow-up
R
 
 
CR - Complete Response
E
             CR                                                  
PR - Partial Response
G
             PR                 CT scans every 6  
months x 1 year
  
PD - Progressive Disease 
   I    RI weekly x              SD 
    
SD - Stable Disease 
S     4 weeks 
 
R - Rituximab 
T                       P D           ( o f f  s t u d y )  
   
I – Imprime PGG 
E  
 
 
 
R
 
 
 
 
  

Imprime PGG and rituximab for relapsed indolent NHL 
November 13, 2018 
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TABLE OF CONTENTS 
1. 
OBJECTIVES ..............................................................................................................1 
1.1 
Study Design ........................................................................................................1 
1.2 
Primary Objectives...............................................................................................1 
1.3 
Secondary Objectives...........................................................................................1 
2. 
BACKGROUND .........................................................................................................1 
2.1 
Imprime PGG .......................................................................................................1 
2.2 
Indolent B cell non-Hodgkin Lymphoma ............................................................5 
2.3 
Rituximab .............................................................................................................5 
2.4 
Rationale for Imprime PGG combined with Rituximab in Indolent NHL ..........6 
3. 
PATIENT SELECTION ..............................................................................................8 
3.1 
Eligibility Criteria ................................................................................................8 
3.2 
Exclusion Criteria ................................................................................................9 
3.3 
Inclusion of Women, Minorities, and other Underrepresented Populations ......11 
4. 
REGISTRATION PROCEDURES ...........................................................................11 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...............................11 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .............................12 
5. 
TREATMENT PLAN ................................................................................................13 
5.1 
Imprime PGG Administration............................................................................13 
5.2 
Rituximab administration...................................................................................13 
5.3 
General Concomitant Medication and Supportive Care Guidelines ..................14 
5.4 
Duration of Therapy ...........................................................................................15 
5.5 
Duration of Follow-up .......................................................................................15 
5.6 
Criteria for Removal from Study .......................................................................15 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .15 
6.1 
Anticipated Toxicities from Imprime PGG .......................................................16 
6.2 
Anticipated Toxicities from Rituximab .............................................................17 
6.3 
Toxicity Management ........................................................................................18 
6.4 
Dose Modifications/Delays ................................................................................19 
7. 
DRUG FORMULATION AND ADMINISTRATION .............................................20 
7.1 
Imprime PGG .....................................................................................................20 
7.2 
Rituximab ...........................................................................................................22 
8. 
CORRELATIVE/SPECIAL STUDIES .....................................................................23 
9. 
STUDY CALENDAR ...............................................................................................24 

Imprime PGG and rituximab for relapsed indolent NHL 
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9.1 
Required data .....................................................................................................26 
9.2 
Required data during study ................................................................................26 
9.3 
Required at end-of-study (EOS) visit (10 weeks +/- 3 days from end of 
treatment) .......................................................................................................................26 
10. MEASUREMENT OF EFFECT................................................................................27 
11. ADVERSE EVENT REPORTING REQUIREMENTS ............................................27 
11.1 
Definitions..........................................................................................................27 
11.2 
Procedures for AE and SAE Recording and Reporting .....................................29 
11.3 
Reporting Requirements ....................................................................................30 
11.4 
Reporting to the Study Sponsor .........................................................................30 
11.5 
Reporting to the Institutional Review Board (IRB) ...........................................32 
11.6 
Reporting to the Food and Drug Administration (FDA) ...................................32 
11.7 
Reporting to Hospital Risk Management ...........................................................32 
11.8 
Monitoring of Adverse Events and Period of Observation ................................33 
12. DATA AND SAFETY MONITORING ....................................................................33 
12.1 
Data Reporting ...................................................................................................33 
12.2 
Safety Meetings .................................................................................................34 
12.3 
Monitoring .........................................................................................................35 
13. REGULATORY CONSIDERATIONS .....................................................................35 
13.1 
Protocol Review and Amendments ....................................................................35 
13.2 
Informed Consent...............................................................................................35 
13.3 
Ethics and Good Clinical Practice (GCP) ..........................................................36 
13.4 
Study Documentation.........................................................................................36 
13.5 
Records Retention ..............................................................................................37 
14. STATISTICAL CONSIDERATIONS.......................................................................37 
14.1 
Study Design/Endpoints.....................................................................................37 
14.2 
Early Stopping- Toxicity....................................................................................37 
14.3 
Sample Size/Accrual Rate ..................................................................................38 
14.4 
Reporting and Exclusions ..................................................................................38 
14.5 
Disclosures and Confidentiality .........................................................................38 
15. PUBLICATION PLAN .............................................................................................38 
16. REFERENCES ..........................................................................................................39 
17. APPENDICES ...........................................................................................................42 
17.1 
APPENDIX A: HYPERSENSITIVITY ALGORITHM ...................................42 

Imprime PGG and rituximab for relapsed indolent NHL 
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17.2 
APPENDIX B: PERFORMANCE STATUS CRITERIA .................................43 
17.3 
APPENDIX C: RESPONSE CRITERIA FOR LYMPHOMA .........................44 
 

Imprime PGG and rituximab for relapsed indolent NHL 
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1.  OBJECTIVES 
 
1.1 
Study Design 
This is a Phase 2 open label single arm study employing a single stage design to assess 
efficacy and safety of Imprime PGG in combination with rituximab in relapsed/refractory 
indolent B cell non-Hodgkin lymphomas (NHL).  The study drug, Imprime PGG, will be 
administered intravenously at a dose of 4mg/kg weekly for 4 weeks. Rituximab will be 
administered intravenously by institutional standards concurrently at a dose of 375mg/m2 
weekly for 4 weeks. Response will be assessed with CT scans 10 weeks +/- 3 days 
following the completion of treatment.   
 
1.2 
Primary Objectives 
 
To evaluate clinical efficacy of Imprime PGG in combination with rituximab in 
relapsed/refractory indolent B cell non-Hodgkin lymphoma (NHL), as measured by the 
overall response rate (ORR) 
 
1.3 
Secondary Objectives 
 
 Determine progression-free survival (PFS) and duration of response.  Evaluate 
safety of this combination in relapsed/refractory indolent NHL patients 
 To perform correlative laboratory studies using on-treatment peripheral blood 
samples and post-treatment tumor samples to quantify the binding of Imprime 
PGG to neutrophils and correlate with treatment response. 
 
 
2. BACKGROUND 
 
2.1 
Imprime PGG 
Imprime PGG is an immunomodulator.  The active ingredient is PGG Beta Glucan, an 
uncharged, water-soluble, beta-glucan polymer purified from the cell wall of a 
proprietary, nonrecombinant strain of Saccharomyces cerevisiae.  Beta glucans are 
polymers of glucose that are extractable from yeasts, fungi (mushrooms), seaweed, and 
some cereals.1 Beta glucans are conserved molecules that are recognized by the human 
innate immune system as non-self molecules. Different forms of beta glucan exist; yeast 
contains beta 1, 3/1, 6 glucan, which is the glucan form in Imprime PGG.  In the case of 
yeast infection, human innate immune cells (e.g., macrophages, monocytes and 
neutrophils) recognize the yeast beta glucan as foreign and initiate an immune response 

Imprime PGG and rituximab for relapsed indolent NHL 
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against the microbe.  An essential step in this response is activation of the complement 
cascade, by antibodies that recognize the yeast as foreign.  This leads to opsonization of 
the yeast cells with iC3b, the inactivated form of complement component 3b, a relatively 
early component in the complement cascade.  Subsequently, the opsonized yeast bind to 
complement receptor 3 (CR3) on innate immune cells, and cytotoxicity follows.  Such 
activity has been shown to require yeast cell interaction with two binding sites on CR3: 
one that binds iC3b on the opsonized yeast cells and a second that binds beta glucan on 
the cell surface of the yeast.2  Dual ligation of the CR3 receptor triggers the innate 
immune effector cells, such as neutrophils, to exert cytotoxic responses against the 
opsonized target. This type of cytotoxicity has been referred to as CR3-dependent cell-
mediated cytotoxicity (CR3-DCC) and differs from traditional ADCC and CDC.3   
It is well understood that anti-tumor monoclonal antibodies, such as rituximab, activate 
the complement system, which would result in the deposition of iC3b on the surface of 
tumor cells. However, leukocyte effector cells would not be expected to exert CR3-DCC 
activity against the tumor cells in the manner that they do against yeast cells because 
mammalian cells do not make or contain beta glucan.  Thus, even though leukocyte CR3 
may recognize the iC3b-opsonized tumor cells, the mechanism of innate cell killing 
described above for yeast would not be activated due to the absence of the second CR3 
signal, i.e., that of beta glucan binding. Thus, administration of beta glucan in 
combination with a monoclonal antibody (MAb) like rituximab should result in CR3-
DCC against tumor cells. This is because 1) MAbs (i.e rituximab) bind to tumor-
associated antigens (i.e. CD20), leading to iC3b opsonization of the tumor cell, and 2) 
beta-glucan binds to CR3 on innate immune effector cells, thus priming them, so that 3) 
the primed immune effector cell can now engage the iC3b-opsonized tumor cell for 
cytotoxicity (i.e., CR3-DCC). 
Pre-clinical studies have demonstrated that combination treatment with beta glucan and 
tumor-specific MAbs induce significant antitumor responses that are superior to either 
agent alone in numerous animal models. 4-8.   Similar enhancement of effects have been 
observed in early clinical trials of Imprime PGG combined with antitumor MAbs9.   
Unpublished results from Biothera study reports of ongoing clinical trials of Imprime 
PGG in combination with cetuximab or bevacizumab with or without chemotherapy in 
colorectal and lung adenocarcinoma are detailed below.  In addition, an ongoing study of 
the combination of Imprime PGG, rituximab and alemtuzumab in patients with high risk 
chronic lymphocytic leukemia (CLL) has produced a 64% complete response rate 
compared to the expected rate of 37% for the MAb treatment alone.9  Imprime PGG is an 
investigational new drug being developed by Biothera in combination with anti-tumor 
MAbs for the treatment of cancer.  The active ingredient in Imprime PGG is PGG Beta 
Glucan.  The inactive ingredients of the drug product are sodium citrate and sodium 
chloride.  The drug product, Imprime PGG, is a sterile solution for IV administration.  It 
is supplied in 20-mL or 50-mL vials containing PGG Beta Glucan at a nominal 
concentration of 1 mg/mL in 0.14 M sodium chloride, 0.011 M sodium citrate, pH 5.0-
7.5.   In preclinical models, the combination of Imprime PGG and tumor-specific mAbs 
results in a dose-dependent anti-tumor and long-term survival-enhancing effect that 
exceed the effects of Imprime PGG or MAb alone.5,8,10 Neutrophils have been shown to 

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be important effector cells of the antitumor activity seen with combination Imprime PGG 
and MAb therapy, and this antitumor activity requires the presence of CR3.10  Blocking 
CR3 prevents Imprime PGG binding to human neutrophils and monocytes in vitro.  This 
data has lead Biothera to develop protocols investigating the combination of Imprime 
PGG and MAbs in the treatment of colon and lung cancer.   
One completed study evaluated the administration of Imprime PGG in combination with 
cetuximab (Erbitux®), with and without standard irinotecan therapy, in metastatic 
colorectal carcinoma (mCRC) subjects.  In this study, subjects were enrolled into dose-
escalating cohorts and dosed with 2 mg/kg, 4 mg/kg, or 6 mg/kg Imprime PGG and a 
standard regimen of cetuximab either with concomitant irinotecan (Arm 1; 10 subjects) or 
without concomitant irinotecan (Arm 2; 22 subjects).  The ORR in Arm #1 was 30% and 
the time to progression (TTP) was 23.7 weeks; these values compared favorably to 
historical ORR and TTP values of 16.4%-22.9% and 17.2-17.6 weeks previously reported 
in mCRC subjects treated with cetuximab and irinotecan.11  The ORR in Arm #2 was 
22.7% and the TTP was 11.7 weeks, also comparing favorably to historical ORR and 
TTP values of 10.8% and 6.5 weeks previously reported in mCRC subjects treated with 
cetuximab monotherapy.11  During the conduct of this study, the importance of tumor 
KRAS gene status in response to cetuximab therapy became known.12  Based on this, 
tumor tissues from the subjects in this study were retrospectively evaluated for KRAS 
status.  ORR and TTP values in the subpopulation of subjects expressing the wild type 
KRAS gene in their tumors were greater than in the overall population, again comparing 
favorably to historical values.  In particular, in Arm #2, ORR and TTP values of 45.4% 
and 23.7 weeks were observed compared to previously reported ORR and TTP values of 
10%-28% and 6.0-15.9 weeks in KRAS wild type subjects treated with cetuximab 
monotherapy.13  These results supported the development of a phase 3 clinical trial in 
KRAS wild type mCRC patients.  In a population of mCRC patients carrying KRAS 
mutation, a phase 2 study has been completed. A total of 18 patients were enrolled and 1 
patient (5.6%) had a partial response (PR), while stable disease (SD) was observed in 9 
additional subjects (50.0%), yielding a disease control rate (DCR) of 55.6%. The median 
overall survival was 6.6 months (range: 1.9-23.1 months). In addition, there are three 
additional ongoing clinical trials of Imprime PGG at a dose of 4mg/kg in combination 
with cetuximab in patients with KRAS mutant mCRC, and in combination with either 
cetuximab or bevacizumab and carboplatin/paclitaxel in the first line treatment of 
advanced non-small cell lung cancer (NSCLC).   
2.1.1 Pharmacokinetics 
 
The pharmacokinetic (PK) profile of Imprime PGG was determined based on the results 
of Phase 1 studies within healthy volunteers (n=36). In general, it was found that, 
elimination of plasma concentrations of beta glucan in healthy adult subjects fit best to a 
three-compartment model.  The “effective” half-life (i.e., the half-life that contributes the 
most to beta glucan disappearance from plasma) was considered to be adequately 
represented by the beta phase, with t1/2β values ranging from 18.1 to 27.0 h.  In a healthy 
volunteer study where Imprime PGG was administered daily for seven consecutive days, 
steady state trough concentrations of beta glucan in plasma and peripheral tissues are 

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observed after 4 days of dosing.  Based on the observed t1/2β, it was determined that a  
dosing interval of once every 7 days will be expected to result in negligible beta glucan 
accumulation in, whereas shorter dosing intervals (e.g., bi-weekly or every 48 h) would 
lead to noticeable accumulation. Based on these results weekly dosing of Imprime PGG 
was chosen for subsequent studies.  PK results from the completed Phase 1b/2 study of 
Imprime PGG in combination with cetuximab ± irinotecan in mCRC (n=32), supported 
the PK results observed in the healthy volunteer studies.  Additional PK data is being 
collected in ongoing Phase 2 studies in advanced stage NSCLC, and in the ongoing Phase 
3 mCRC study, however, have not yet been analyzed.    
 
2.1.2 Clinical Experience 
The clinical experience with Imprime PGG has included three Phase 1 studies of Imprime 
PGG alone or in combination with G-CSF in healthy volunteers; a Phase 1b/2, a Phase 2, 
and an ongoing Phase 3 study of Imprime PGG in combination with cetuximab for the 
treatment of mCRC; and two Phase 2 studies of Imprime PGG in combination with 
cetuximab or bevacizumab + chemotherapy for the treatment of NSCLC.  In total 85 
healthy volunteers and approximately 250 cancer patients have received at least one dose 
of Imprime PGG. 
 
2.1.3 Safety 
In general, Imprime PGG was very well tolerated when administered alone or in 
combination with G-CSF, anti-tumor MAbs, and/or chemotherapy.  In studies involving 
healthy volunteers, while a majority of patients (84%) experienced at least 1 adverse 
event (AE), none of these were considered severe.  Among the cancer studies, nearly all 
patients experienced at least one AE but the majority of these were deemed unlikely to be 
related to the study drug, and the number of patients who discontinued treatment due to 
AEs ranged from 0% to 49%.  The AEs responsible for study discontinuation included 
most commonly allergic reactions and rash, but also pancreatitis, delayed wound healing, 
bilateral conjunctivitis, pleural effusion, suspected hypertrophic cardiomyopathy, and 
back pain. 
 
Common adverse reactions (≥ 5% in Imprime PGG-treated subjects) in clinical trials of 
healthy volunteers included headache, back pain, chest pain, dyspnea, abdominal pain, 
arthralgia, nausea, injection site pain, musculoskeletal pain, pain in extremity, and 
urticaria.  Fewer than 5% of patients experienced infusion reactions (dizziness, 
paraesthesia, rash, nausea, and flushing), fatigue, myalgia, and diarrhea. 
 
Serious AEs (SAE) have been reported in anywhere from 25%-90% of cancer patients 
depending on the study, with the exception of two single-IND studies, where the 
respective SAE rates were 0% and 100%.  In studies including a control arm, the rate of 
SAEs is slightly lower in the Imprime PGG arm (27.3% v 41.7% and 36.4% v 44.0%) in 
two of the studies, and slightly higher in the Imprime PGG arm n one study (61.7% v 
40%).  SAEs that have been reported in more than one patient per study include general 

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health decline, nausea, pneumonia, pneumothorax, diarrhea, dyspnea, lung embolism, 
neutropenia, pleural effusion, and pulmonary embolism.  Among these, the following 
occurred in more than 5% of patients: general health decline (6.8%), diarrhea (6.7%), 
neutropenia (6.7%), and pleural effusion (6.7%). Eighteen (18) deaths have been reported 
in studies with Imprime PGG, including one that occurred prior to a subject receiving any 
study-related medications.  Of these, 15 deaths occurred in the NSCLC studies: 7 in 
LCA0821 (Imprime PGG with bevacizumab + chemotherapy) and 8 in LCA0822 
(Imprime PGG with cetuximab + chemotherapy). In LCA0821, deaths were the outcome 
of general health deterioration (N=3, investigational arm), disease progression (N=1, 
investigational arm), intracranial hemorrhage (N=1, investigational arm), pneumonia 
(N=1, investigational arm), and pneumothorax (N=1, investigational arm). In LCA0822, 
deaths were the outcome of sepsis following severe neutropenia and acute renal failure 
(N=1, investigational arm), acute cardiovascular failure (N=1, investigational arm), 
disease progression (N=1, control arm), hemoptysis (N=2, investigational arm), pleural 
effusion (N=1, investigational arm), and pulmonary hemorrhage (N=1, investigational 
arm). To date, three deaths have occurred in study CRC1031 (Phase 3 mCRC). The 
deaths were the outcome of bilateral bowel perforation (N=1, investigational arm), 
cardiac arrest (N=1, investigational arm), and pneumonia (N=1, investigational arm). 
 
In dose escalation studies (2mg/kg, 4mg/kg and 6mg/kg); no maximally tolerated dose 
has been achieved.  Biothera has opted to proceed with the 4mg/kg dose based on 
tolerability and efficacy data showing that this dose is more efficacious than the 2mg/kg 
and 6mg/kg doses.  
 
2.2 
Indolent B cell non-Hodgkin Lymphoma 
There will be approximately 70,130 new cases of NHL this year in the United States, and 
18,940 deaths. The indolent NHLs, including follicular lymphoma and marginal zone 
lymphoma, generally present at advanced stage and are incurable with conventional 
therapies. Though incurable, these diseases tend to be chemotherapy responsive with high 
rates of initial response, but they exhibit progressively lower rates of response and 
remission duration with subsequent lines of therapy, and always with invariable relapse. 
Available therapies for indolent NHLs include single-agent and combination 
chemotherapy, monoclonal antibody based therapy, radiotherapy, radioimmunotherapy, 
and stem cell transplantation in selected cases. 
 
2.3 
Rituximab 
 
Of the many effective treatment modalities for indolent NHL, overall survival benefits 
have not been demonstrated favoring one treatment approach over another, with the 
exception of rituximab-containing chemotherapy versus chemotherapy alone. Increased 
intensity regimens have been shown to improve complete response rates and progression 
free survivals without improvement in overall survival. Choice of therapy has thus been 
based upon balancing efficacy and tolerability. Available treatment approaches currently 

Imprime PGG and rituximab for relapsed indolent NHL 
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employed in chemotherapy naïve and relapsed/refractory patients include rituximab 
monotherapy, R-bendamustine, R-CVP (rituximab, cyclophosphamide, vincristine, 
prednisone), R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, 
prednisone), fludarabine-based regimens, radioimmunotherapy, and occasionally single 
agent oral alkylator therapy. Single agent monoclonal antibodies are an attractive 
treatment option given excellent tolerability. Rituximab is approved as a single agent in 
relapsed or refractory low grade or follicular non-Hodgkin’s lymphoma (NHL) and in 
combination with chemotherapy for first line therapy of follicular NHL and diffuse large 
B cell lymphoma (DLBCL).   
 
Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody 
directed against the CD20 antigen found on the surface of normal and malignant pre-B 
and mature B cells. The antibody is an IgG1 κ immunoglobulin containing murine light 
and heavy-chain variable region sequences and human constant region sequences. 
Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 
213 amino acids (based on cDNA analaysis) and has an approximate molecular mass of 
145 kD. Rituximab has a binding affinity for the CD20 antigen of ~8.0 nM.  Several 
mechanisms of action have been proposed in various models including complement-
dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytoxicity (ADCC), 
induction of apoptosis, and a “vaccinal” effect.14  It is likely that rituximab works through 
a combination of these mechanisms. 
 
The overall response rate for rituximab monotherapy in relapsed low-grade B-cell 
lymphoma is approximately 24-36% with complete response rates of approximately 
7%.15  Several mechanisms for rituximab resistance have been proposed including 
variable CD20 expression by lymphoma subtype, variability in complement activation, 
and polymorphisms in Fc receptors.16-18  Novel agents that overcome these resistance 
mechanisms might offer similar complete response rates to combined chemotherapy and 
immunotherapy with improved tolerability. 
 
2.4 
Rationale for Imprime PGG combined with Rituximab in Indolent NHL 
 
Rituximab is a highly efficacious and tolerable therapy for the treatment of indolent 
NHL, but response rates fall in the relapsed setting with some patients developing 
refractory or rituximab-resistant disease.  The mechanism of this resistance is unknown 
but has been proposed to be related to variability in complement activation, variable 
CD20 expression, and polymorphisms in the Fc receptors.16-18  Although complement 
activation and CDC is not absolutely necessary for rituximab-induced cytotoxicity, loss 
of complement has been shown to reduce its anti-tumor effect in mouse models.19,20  
Conversely, inhibition of membrane-bound inhibitory proteins of the complement 
cascade facilitates rituximab’s effect on NHL.20  CDC is a more potent anti-tumor 
mechanism when the immune target is present in higher numbers on the cell surface, and 
this has been shown to be true for rituximab and CD20 on the lymphoma cell surface.21,22  
Complement activation, then, can be enhanced by mechanisms that increase CD20 

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expression in the tumor cell, or by using immune adjuncts to enhance complement 
activity, or antibodies against iC3b to increase iC3b deposition.  
 
Another way to increase anti-tumor cytotoxicity of complement depositing antibodies is 
to increase the recognition of tumor-bound iC3b by innate immune cells.   As outlined 
above, Imprime PGG is the yeast-derived beta 1, 3/1, 6 glucan that is recognized by, and 
facilitates an immune response by, human innate immune cells (e.g., macrophages, 
monocytes and neutrophils) in the setting of a yeast infection.  CR3-DCC, the 
cytotoxicity that occurs as a result of the necessary coincident binding of CR3 on innate 
immune cells by iC3b and beta glucan on opsonized yeast cells, differs from traditional 
ADCC and CDC and can be exploited to enhance tumor cell killing by antibody 
therapies.3  This can be accomplished by the coadministration of a compound like 
Imprime PGG with an anti-tumor MAb, which allows innate immune cells to recognize 
iC3b opsonized tumor cells through their complement receptor 3 (CR3).23,24  The 
coadministration of the two drugs takes advantage of the fact that tumor cell-MAb 
binding activates the complement system resulting in iC3b deposition on the tumor cells.  
However, leukocyte effector cells would not be expected to exert CR3-DCC activity 
against the tumor cells in the manner that they do against yeast cells because mammalian 
cells do not make or contain beta glucan, a molecule whose binding to CR3 is necessary 
to provide the second signal to activate the immune effector cell.  The co-administration 
of beta glucan, however, in combination with a MAb like rituximab should result in CR3-
DCC against tumor cells. This is because 1) MAbs (i.e rituximab) bind to tumor-
associated antigens (i.e. CD20), leading to iC3b opsonization of the tumor cell, and 2) 
beta-glucan binds to CR3 on innate immune effector cells, thus priming them, so that 3) 
the primed immune effector cell can now engage the iC3b-opsonized tumor cell for 
cytotoxicity (i.e., CR3-DCC).  
Clinical data from phase 1 and 2 studies in colorectal and lung cancer outlined above 
support this synergistic mechanism of action, and an ongoing phase 3 clinical trial of 
Imprime PGG and cetuximab in mCRC is underway.  This has also been investigated in 
mouse models of NHL and Hodgkin’s disease treated with (1-3),(1-4)-β-D-glucan (BG) 
in combination with rituximab, or BG or rituximab alone.4  Specifically, subcutaneous 
and disseminated xenograft models were developed using the human Burkitt lymphoma 
cell line, Daudi, and the Hodgkin’s disease cel lines Hs445 and RPMI 6666.  
Combination therapy with BG and rituximab resulted in greater suppression of tumor 
growth in the subcutaneous xenografts that persisted beyond treatement, and improved 
survival in both the subcutaneous and disseminated xenografts compared with either drug 
alone and no clinical toxicity was observed.  Among the disseminated xenografts, 
approximately one quarter of the mice receiving the combination therapy were alive at 
one year, consistent with eradication of disease, compared to no mice who received 
rituximab alone.  That BG interacted with effector leukocytes was confirmed by 
intracellular detection by immunofluorescence.  Responses were greatest in Daudi 
xenografts, perhaps relating to the fact that Burkitt lymphoma has higher CD20 
expression than Hodgkin lymphoma, although tumor progression was not associated with 
loss of CD20.  In addition, an ongoing phase I clinical trial of alemtuzumab, rituximab, 

Imprime PGG and rituximab for relapsed indolent NHL 
November 13, 2018 
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and Imprime PGG in CLL resulted in a complete response rate of 64% (7/11) compared 
to a historical rate of 37% for alemtuzumab and rituximab alone.9  In this study there 
were three dose cohorts for Imprime PGG (1mg/kg, 2mg/kg, and 4mg/kg) with the 
maximally tolerated dose being 4mg/kg and the combination being well tolerated.  Taken 
together this data supports an exploration of Imprime PGG and rituximab in indolent B 
cell lymphomas that might otherwise be treated with rituximab alone. 
 
We hypothesize that combining Imprime PGG with rituximab for the treatment of 
relapsed and refractory indolent B cell NHL should result in an improvement in response 
rates.  By collecting pre- and on treatment peripheral blood samples from patients, we 
will be able to categorize the percentage of Imprime PGG-bound and activated 
neutrophils,and correlate this with responses to treatment.  .   
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Patients must have histologically determined indolent NHL that is relapsed 
or primary refractory after initial therapy. Indolent NHL includes the 
morphologic and clinical variants: 
 Follicular lymphoma, grades 1-3a  
 Marginal zone lymphoma (extranodal, nodal, or splenic) 
o All nodal marginal zone lymphomas are eligible 
o Extranodal marginal zone lymphomas of the stomach (gastric 
MALT lymphomas) may not be candidates for cure with 
antibiotics or local radiotherapy. Patients who have failed 
antibiotics or local therapy are eligible for the protocol as long 
as they have measurable disease \. 
o Splenic marginal zone lymphoma patients may have received 
prior splenectomy as long as they have measurable disease. 
 Re-biopsy is not mandated at relapse unless there is clinical suspicion 
about an alternate diagnosis.   
 
3.1.2 One or more prior lines of chemoimmunotherapy and/or monotherapy with 
rituximab or other anti-CD20 antibody.  Patients may have had a prior 
autologous stem cell transplant but not prior allogeneic stem cell 
transplantation. 
 

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3.1.3 Measurable disease that has not been previously irradiated on CT scans of at 
least 2 cm, OR if the patient has had previous radiation to the marker 
lesion(s), there must be evidence of progression since the radiation. Imaging 
must be completed no greater than 6 weeks prior to study enrollment. 
 
3.1.4 ECOG performance status 0-2 (Appendix B, Section 17.2) 
 
3.1.5 Absolute neutrophil count > 750 prior to treatment 
 
3.1.6 Oxygen saturation ≥90%, no more than 2 LPM oxygen 
 
3.1.7 Serum creatinine ≤ 1.5 X ULN 
 
3.1.8 AST ≤ 3 X ULN 
 
3.1.9 Total bilirubin ≤ 1.5 X ULN (unless there is lymphoma in the liver) 
 
3.1.10 Age >18 years 
 
 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.2 
Exclusion Criteria 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study. 
 
3.2.1 Patients currently receiving anticancer therapies or who have received 
anticancer therapies within 30 days of the start of study drug (including 
chemotherapy, radiation therapy, antibody based therapy, etc.). Steroids for 
symptom palliation are allowed, but must be either discontinued or on stable 
doses at the time of initiation of protocol therapy. 
 
3.2.2 Patients may not be receiving any other investigational agents, or have 
received investigational agents within 4 weeks of beginning treatment. 

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3.2.3 Patients who have previously received PGG-Betafectin (Betafectin®) or 
Imprime PGG. 
 
3.2.4 Patients, who have had a major surgery or significant traumatic injury 
within 4 weeks of start of study drug, patients who have not recovered from 
the side effects of any major surgery (defined as requiring general 
anesthesia) or patients that may require major surgery during the course of 
the study. 
 
3.2.5 Patients with known leptomeningeal or brain metastases. Imaging or spinal 
fluid analysis to exclude CNS involvement is not required, unless there is 
clinical suspicion by the treating investigator. 
 
3.2.6 History of severe allergic or anaphylactic reactions to monoclonal antibody 
therapy or a known hypersensitivity to baker’s yeast, unless in consultation 
with an allergy specialist they are deemed eligible for retreatment with 
desensitization. 
 
3.2.7 Patients with known HIV infection or hepatitis B or C infection.HIV testing 
is not mandated and is to be performed at the discretion of the treating 
investigator. 
 
3.2.8 Patients with a systemic fungal, bacterial, viral, or other infection not 
controlled (defined as exhibiting ongoing signs/symptoms related to the 
infection and without improvement, despite appropriate antibiotics or other 
treatment). 
 
3.2.9 Prior history of another malignancy (except for non-melanoma skin cancer 
or in situ cervical or breast cancer) unless disease free for at least three 
years. Patients with prostate cancer are allowed if PSA is less than 1.  
Patients with indolent malignancies under control and which, in the opinion 
of the treating investigator, are unlikely to be clinically relevant or affect 
survival during the course of the study treatment and follow-up. 
 
3.2.10 Patients should not receive immunization with attenuated live vaccine 
within one week of study entry or during study period. 
 

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3.2.11 Female patients who are pregnant or breast feeding, or adults of 
reproductive potential who are not using effective birth control methods. 
Women of child bearing potential (WOCBP) or male study participants of 
reproductive potential must agree to use double barrier birth control method 
of contraception during the course of the study treatment period and for 3 
months after completing study treatment.  
 
WOCBP are defined as sexually mature women who have not undergone a 
hysterectomy or who are not postmenopausal (no menses) for at least 12 
consecutive months. WOCBP must have a negative urine or serum pregnancy 
test within 7 days prior to administration of treatment. 
 
3.2.12 History of noncompliance to medical regimens. 
 
3.2.13 Patients who have any severe and/or uncontrolled medical conditions or 
other conditions that could affect their participation in the study such as: 
- New York Heart Association Class III or IV cardiac disease, including 
pre-existing clinically significant arrhythmia, congestive heart failure, or 
cardiomyopathy 
- unstable angina pectoris, symptomatic congestive heart failure, 
myocardial infarction within 6 months of start of study drug, serious 
uncontrolled cardiac arrhythmia or any other clinically significant 
cardiac disease 
 
3.2.14 Other uncontrolled intercurrent illness that would limit adherence to study 
requirements. 
 
3.3 
Inclusion of Women, Minorities, and other Underrepresented Populations 
 
Women, minorities and underrepresented populations should be eligible for this trial at a 
similar rate to men and patients not from underrepresented populations.  The inclusion 
and exclusion criteria should not be affected by gender or ethnicity, except for the 
exclusion of pregnant or lactating women. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 

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occur prior to the initiation of therapy. Any participant not registered to the 
protocol before treatment begins will be considered ineligible and registration will 
be denied. 
 
A member of the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the Principal Investigator. 
If a participant does not receive protocol therapy following registration, the 
participant’s protocol status must be changed. Notify the QACT Registrar of 
participant status changes as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 
AM to 5:00 PM Eastern Standard Time. If a participant must be registered during 
off-hours or holidays, call the QACT registration line at 617-632-3761 and follow 
the instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
1.   Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2.   Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as 
eligibility for the treatment study. Registration to both treatment and ancillary 
studies will not be completed if eligibility requirements are not met for all 
studies. 
 
3.   Fax the eligibility checklist(s) and all pages of the consent form(s) to the 
QACT at 617-632-2295. 
 
4.   The QACT Registrar will (a) validate eligibility, (b) register the participant on 
the study, and (c) randomize the participant when applicable. 
5.   The QACT Registrar will send an email confirmation of the registration 
and/or randomization to the person initiating the registration immediately 
following the registration and/or randomization. 
 

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5. TREATMENT PLAN 
 
It is expected that treatment will be administered on an outpatient basis.  Therapy will 
consist of four weekly treatments of both Imprime PGG (4mg/kg/dose) and 
rituximab (375 mg/m2/dose). Imprime PGG will be administered first, followed by a 
minimum waiting time of 10 to 15 minutes (but maximum of 24 hours +/- 4 hours) before 
the start of rituximab. Patients with bulky disease or circulating disease ≥ 15,000 
circulating malignant cells/ mm3 will receive allopurinol for prophylaxis of tumor lysis 
syndrome. Response will be assessed 10 weeks after the completion of therapy by CT 
scans of the chest, abdomen, and pelvis. Expected toxicities and potential risks for 
Imprime PGG and rituximab are described in Section 6 (Expected Toxicities and Dosing 
Delays/Dose Modifications).  No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the participant's 
malignancy.  
 
5.1 
Imprime PGG Administration 
 
The study drug Imprime PGG will be administered by intravenous bolus infusion through 
a low protein binding 0.22-micrometer in-line filter at a dose of 4 mg/kg (actual body 
weight) over at least 2 hours (longer infusion times are required for subjects over 75 kg).  
The dosing frequency will be every 7 days for a total of 4 weeks.  Participants will be 
pre-medicated according to institutional standards for rituximab prior to administration of 
either drug.  Imprime PGG will be provided by Biothera.  The drug product, Imprime 
PGG, is a sterile solution for IV administration.  It is supplied in 20-mL or 50-mL vials 
containing PGG Beta Glucan at a nominal concentration of 1 mg/mL in 0.14 M sodium 
chloride, 0.011 M sodium citrate, pH 5.0-7.5.  
5.2 
Rituximab administration 
 
Rituximab from a commercial supply will be administered IV at a dose of 375 mg/m2 
every 7 days for 4 weeks.  Actual body weight will be measured prior to each Rituximab 
infusion to calculate the BSA and dose for each infusion..  If the infusion cannot be 
completed within 1 day, the patient is allowed to receive the remainder of the infusion the 
following day as long as the dose is administered within 2 consecutive days. 
 
Rituximab will be administered at DFCI per Dana-Farber Harvard Cancer 
Center institutional guidelines.  
 
Dana-Farber Harvard Cancer Center institutional guidelines include: 
 

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 Participants will be pre-medicated with hydrocortisone 100 mg IV, 
acetaminophen 650 mg, and diphenhydramine 25 mg PO, or their equivalents, 
prior to each dose.  
 No specific prehydration is required.  
 The first infusion will begin at an initial rate of 50 mg/hour for the first hour. If 
hypersensitivity or infusion-related events do not occur, the rate will be increased 
in 50 mg/hour increments every 30 minutes until a maximal rate of 400 mg/hour.  
 On subsequent infusions the initial rate in the absence of hypersensitivity will be 
20 percent of the total dose over 30 minutes, followed by the remaining 80 
percent of the total dose over 60 minutes.  
 Vital signs should be checked approximately every 15 minutes during the first 
hour of infusion, then approximately once an hour or prior to any infusion rate 
change until completion of the infusion.  
 Infusion should be temporarily discontinued for a temperature > 101.3oF, mucosal 
edema, or >30 mm Hg decrease in systolic blood pressure.  
 An additional 25 mg of benadryl IV should be given.  
 Infusion may resume after symptoms resolve a 50% of the rate infusing at the 
time of the event. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
5.3.1 Pre-medications 
Participants will be premedicated with hydrocortisone 100 mg IV, acetaminophen 
650 mg, and diphenhydramine 25 mg PO, or their equivalents, prior to each dose. No 
specific prehydration is required. 
 
5.3.2 Antibiotics 
Prophylactic antibiotics or anti-virals are not required on this trial. 
 
5.3.3 Hydration 
No pre-hydration or hydration is required with this regimen. 
 
5.3.4 Tumor lysis prevention and management 
Participants with bulky disease and/or circulating disease ≥ 15,000 circulating 
malignant cells/ mm3 may receive allopurinol 300mg orally daily for 7-10 days 
starting with the first dose of Imprime PGG and rituximab.  Participants deemed at 
risk for tumor lysis syndrome (TLS) should have their labs monitored per standard 
practice.  The management of established TLs should also follow standard practice. 
 

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5.3.5 Other 
Blood product transfusions and the use of bisphosphonates are permitted at the 
discretion of the treating physician. 
 
5.4 
Duration of Therapy 
 
Duration of therapy will be for four weeks but will be stopped in the event of any of the 
following: 
 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Participant demonstrates and inability or unwillingness to comply with the 
medication regimen and/or documentation requirements 
 Participant decides to withdraw from the study 
 General or specific changes in the participant’s condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator 
 
5.5 
Duration of Follow-up 
 
Participants who have received at least one dose of Imprime PGG and Rituximab will be 
followed for 1 year after the completion of combination therapy or until death, whichever 
comes first..  Participants removed from the study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event.  The post-treatment visit 
(Section 9) will occur 10 weeks +/- 3 days from the last day of treatment.    
 
 
5.6 
Criteria for Removal from Study Treatment  
Participants will be removed from study when any of the criteria listed in Section 5.4 
applies.  The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Caron Jacobson, M.D. at 617-632-3352. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE 
MODIFICATIONS 
 
Dose delays and modification will be made using the recommendations in Section 6.3.  
Toxicity assessments will be done using the Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) which is identified and located on the 

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CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If possible, symptoms should be managed symptomatically.  In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, 
etc). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of the study treatment, through the study and until the final study visit.  Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
6.1 
Anticipated Toxicities from Imprime PGG 
 
A list of the adverse events and potential risks associated with Imprime PGG appear 
below and will determine whether dose delays and modifications will be made or whether 
the event requires expedited reporting in addition to routine reporting.   
 
 Less likely toxicities (5-20%) 
o Increase in Aspartate Aminotransferase (AST) and Alkaline phosphate 
(ALK) levels in the blood 
o Skin rash or dry skin 
o Diarrhea 
o Electrolyte disturbances: decrease in potassium, magnesium, and/or 
phosphate levels in the blood 
o Hair loss 
o Anemia 
o Decreased appetite 
o Increase in amylase levels in the blood 
o Headache 
o Allergic reaction 
o Hypertension 
o Dyspnea 
o Conjunctivitis  
o Increased or decreased number of white blood cells 
o Mouth sores 
o Nausea or vomiting 
o Swelling around finger nails 
o Arthralgia 
o Fever 
 

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 Rare but serious toxicities (<5%) 
o Dehydration 
o Fluid around the lungs 
o Blood clot that travels to the lungs 
o Death (refer to Section 2.1.1.3) 
 
 
6.2 
Anticipated Toxicities from Rituximab 
A list of the adverse events and potential risks associated with rituximab appear below 
and will determine whether dose delays and modifications will be made or whether the 
event requires expedited reporting in addition to routine reporting.   
 
 Infusion reactions: including fever, chills, headache, nausea, vomiting, throat 
irritation, flushing, rash, pruritis, urticaria, dyspnea, increased cough, rhinitis, 
asthenia, and hypotension, primarily during rituximab infusions which typically 
respond to an interruption of the infusion and resumption at a slower rate. 
 Fatal Infusion Reactions: Severe and fatal cardiopulmonary events, 
including angioedema, hypoxia, pulmonary infiltrates, acute respiratory 
distress syndrome, myocardial infarction, and cardiogenic shock, have 
been reported. These severe reactions typically occurred during the first 
infusion with time to onset of 30-120 minutes. 
 Night sweats 
 Abominal pain, pain, back pain 
 Sinusitis 
 Diarrhea 
 Myalgia 
 Arthralgia 
 Hypertension 
 Dizziness 
 Anxiety 
 Tumor Lysis Syndrome: tumor lysis syndrome has been reported and is 
characterized in patients with a high number of circulating malignant cells 
(≥25,000 ul) by rapid reduction in tumor volume, renal insufficiency, 
hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatemia. 
 Mucocutaneous Reactions: Severe bullous skin reactions, including fatal cases of 
toxic epidermal necrolysis and paraneoplastic pemphigus, have been reported. 
The onset of reaction has varied from 1 to 13 weeks following rituximab 
exposure. 
 Metabolic Events: Hyperglycemia, peripheral edema, LDH increase 
 Hematologic Events: including  lymphopenia, neutropenia, leukopenia, 
thrombocytopenia with a median duration of approximately 14 days.  Transient 
aplastic anemia (pure red cell aplasia) and hemolytic anemia have been reported.  

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Late onset neutropenia, marrow hypoplasia, and prolonged pancytopenia have 
also been reported. 
 Infectious Events: B cell depletion and decreased serum immunoglobulins have 
been associated with an increased risk of bacterial and viral infections.  Serious 
infections (grade 3 or 4) are rare, occurring in approximately 2% of patients. 
 Hepatitis B Reactivation: Hepatitis B virus (HBV) reactivation with 
fulminant hepatitis, hepatic failure, and death has been reported in some 
patients with hematologic malignancies treated with rituximab. The 
majority of patients received rituximab in combination with 
chemotherapy. The median time to the diagnosis of hepatitis was 
approximately four months after the initiation of rituximab and 
approximately one month after the last dose. 
 Other Serious Viral Infections: including JC virus (progressive multifocal 
leukoencephalopathy [PML]), cytomegalovirus, herpes simplex virus, 
parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In 
some cases, the viral infections occurred up to one year following 
discontinuation of Rituximab and have resulted in death. 
 Progressive multifocal leukoencephalopathy (PML): PML is a rare and 
demyelinating disease of the brain caused by infection with the JC virus that 
usually leads to death or severe disability. JC virus infection resulting in PML and 
death has been reported rarely in patients with hematologic malignancies 
receiving rituximab. The majority of these patients had received rituximab in 
combination with chemotherapy or as part of a hematopoietic stem cell transplant.  
 
The following serious adverse events have been reported to occur in 
patients following completion of rituximab infusions: arthritis, disorders of blood 
vessels (vasculitis, serum sickness and lupus-like syndrome), eye disorders 
(uveitis and optic neuritis), lung disorders including pleuritis and scarring of the 
lung (bronchiolitis obliterans), that may result in fatal outcomes, and fatal cardiac 
failure. 
 
6.3 
Toxicity Management 
 
Toxicity management should follow standard clinical practice.  Specific 
recommendations that apply to both Imprime PGG and rituximab follow: 
 
6.3.1 Infusion toxicity 
 
Infusion should be temporarily discontinued for a temperature > 101.3F, mucosal 
edema, or >30 mm Hg decrease in systolic blood pressure. Hypersensitivity 
reactions should be treated per DFCI institutional guidelines (See Appendix A). If  
hypersensitivity occurs, an additional 25 mg of diphenhydramine IV should be 
given. Participants with hypersensitivity should also receive methylprednisolone 
50 mg IVB and ranitidine 50 mg IVB. Participant with bronchospasm should be 

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treated with supplemental oxygen and nebulizers as needed. Infusion may resume 
after symptoms resolve at 50% of the rate infusing at the time of the event. 
 
Participants with life threatening infusional reactions including cardiac 
arrhythmia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial 
infarction, cardiogenic shock, or anaphylactoid events should not be re-challenged 
and should be removed from study. No dose reductions will be made for 
infusional reactions.  Section 6.4 outlines the protocol for dose delays in the 
setting of an infusion reaction to either agent. 
 
6.3.2 Hematologic toxicities 
 
The only hematologic parameter that must be met on each treatment day is an 
ANC >1000.  Hematologic toxicities should be managed by standard use of 
transfusions and growth factors.  In particular, white blood cell growth factor use 
(e.g., neupogen) is acceptable on this study.  A dose delay of up to 1 week for 
recovery of neutropenia to an ANC >1000 is acceptable on this study. 
 
6.3.3 Non-hematologic toxicities 
 
In the case of asymptomatic laboratory abnormalities (e.g., LFT abnormalities), 
no intervention is required.  Symptomatic abnormalities should be managed using 
standard clinical guidelines. 
 
6.4 
Dose Modifications/Delays 
 
No dose reductions will be made. Participants unable to tolerate the specified dose of 
either Imprime PGG or rituximab will be removed from study. Imprime PGG and/or 
rituximab infusion should be interrupted for severe reactions, e.g., rapid tumor lysis. 
Treatment of infusion-related symptoms with diphenhydramine and acetaminophen is 
recommended. Additional treatment with bronchodilators or IV saline may be indicated. 
Epinephrine, antihistamines, and corticosteroids should be available for immediate use in 
the event of a hypersensitivity reaction to rituximab (e.g., anaphylaxis). In most cases, the 
infusion can be resumed at a 50% reduction in rate from the last known rate (e.g., from 
100mg/hr to 50mg/hr) when symptoms and laboratory abnormalities have completely 
resolved. Infusions should be discontinued in the event of serious or life-threatening 
cardiac arrhythmias. Subjects who develop clinically significant arrhythmias should 
undergo cardiac monitoring during and after subsequent infusions.  Whether to 
discontinue the infusion and when to restart the infusion of either agent following a non-
life threatening infusion reaction is up to the discretion of the treating physician.  In the 
event of a non-life threatening infusion reaction to Imprime PGG, patients must be 
rechallenged within one week, and rituximab may be delayed by up to 24 hours following 
the successful infusion of Imprime PGG.  In the event of a non-life threatening infusion 

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reaction to rituximab, dosing of Imprime PGG and rituximab may be delayed by up to 
one week. 
 
A temporary delay of all study dosing may occur if the subject’s health precludes study 
drug administration (i.e., subject is experiencing an adverse event that requires 
hospitalization; ANC <750.)  Subjects that require permanent discontinuation of 
rituximab, or fail to receive any rituximab for >7 consecutive days from the missed dose, 
or > 14 consecutive days in total, should discontinue all study drug administration.  
 
Participants will be removed from study when any of the criteria listed in Section 5.4 
apply. The reason for study removal and the date the participant was removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be 
discussed with the participant. 
 
7. DRUG FORMULATION AND ADMINISTRATION 
 
7.1 
Imprime PGG 
 
7.1.1 Drug product formulation 
 
Imprime PGG is supplied in 20-mL and 50-mL Type I clear borosilicate glass vials.  
Each vial contains PGG Beta Glucan at a nominal concentration of 1 mg/mL in a citrate-
buffered saline solution (pH 5.0-7.5).  Vials are filled to a target volume of 21.2 mL to 
ensure a deliverable amount of 20 mL per vial.  
The active ingredient of the drug product is the beta glucan polymer, PGG Beta Glucan.  
The inactive ingredients of the drug product are sodium citrate and sodium chloride. 
 
7.1.2 Storage 
 
Imprime PGG should be stored between 15C and 27C. 
7.1.3 Compatibility 
 
Imprime PGG, is a sterile solution for IV. infusion.  The appropriate dose based on body 
weight will be diluted by the site pharmacist in 0.9% Sodium Chloride so that the total 
volume of Imprime PGG and 0.9% Sodium Chloride equals the volumes specified below 
for strata of body weight in Section 7.1.6 Preparation and Route of Administration. 
 
7.1.4 Handling 
 

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Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the chemotherapeutic agent in a self-contained and protective environment. 
 
7.1.5 Availability 
 
Imprime PGG is an investigational agent and will be supplied free-of-charge from 
Biothera. 
 
7.1.6 Preparation and Route of Administration 
 
Imprime PGG, is a sterile solution for IV infusion.  The appropriate dose based on body 
weight will be diluted by the site pharmacist in 0.9% Sodium Chloride so that the total 
volume of Imprime PGG and 0.9% Sodium Chloride equals the volumes specified below 
for strata of body weight.   
Subject Weight in 
Kilograms 
Imprime PGG 
Dose (mg/kg) 
Total Infusion 
Volume (mLs) 
Total Infusion 
Time (hours) 
Rate of Infusion 
 (mL/min) 
75 kgs 
4 mg/kg 
500 mLs 
2 hours (+/- 10 min) 
4.2 mLs/min 
75 to 150kgs 
4 mg/kg 
750 mLs 
3 hours (+/- 10 min) 
4.2 mLs/min 
150 kgs 
4 mg/kg 
1000 mLs 
4 hours (+/- 10 min) 
4.2 mLs/min 
 
The final volume will be administered by IV infusion at a rate of 4.2mL/min (total time 
to be determined by the total infusion volume) with a +/- 10 minute window.  An infusion 
pump will be used to assure accurate and consistent dosing.  Imprime PGG is supplied in 
20-mL or 50-mL vials containing 20mg or 50mg, respectively, of Imprime PGG (1 
mg/mL). The total storage time of Imprime PGG diluted in the IV bags, inclusive of 
administration, cannot exceed 8 hours at room temperature or 24 hours at 2-80C. 
 
7.1.7 Ordering 
 
Imprime PGG for this study will be ordered from Biothera.  Ordering can be done with a 
templated reorder form from Biothera, sent to Email: kbreuer@biothera.com or Fax: 
(651) 675-0400; Attn: Kelly Breuer.  
 
7.1.8 Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 

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Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.) 
 
7.1.9 Destruction and Return 
 
At the end of the study, unused supplies of [agent] should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record 
Form. 
 
7.2 
Rituximab 
 
7.2.1 Drug Product Information 
 
Rituximab is commercially available and will be provided as an infusion prepared by a 
site pharmacist. Please refer to the FDA-approved package insert for rituximab for 
product information. 
 
 
 
 
7.2.2 Storage 
 
Intact vials should be stored under refrigeration. Dilute solutions for infusion (1-4 
mg/mL) are stable for 24 hours under refrigeration, and for an additional 24 hours at 
room temperature. 
 
7.2.3 Availability 
 
Rituximab is commercially available in 10 mL and 50 mL single-use vials containing 100 
or 500 mg of rituximab solution, respectively, at a concentration of 10 mg/mL. Please 
refer to the agent’s package insert for additional information. 
 
7.2.4 Preparation and Route of Administration 
 
The desired dose of rituximab should be diluted in 0.9% NaCl or D5W to a final 
concentration of 1-4 mg/mL. Mix by inverting the bag gently.  Rituximab will be 
administered by IV infusion. Participants must be  premedicated with hydrocortisone 
100 mg IV, acetaminophen 650 mg, and diphenhydramine 25 mg PO, or their 
equivalents, prior to each dose. No specific prehydration is required. 
 

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7.2.5 Destruction and Return 
 
At the end of the study, unused supplies of [agent] should be destroyed according to 
institutional policies. Destruction will be documented and drug accountability for 
rituximab will not be documented since this drug will be charged to patients insurance.    
 
8. CORRELATIVE/SPECIAL STUDIES 
Participants will have one pretreatment peripheral blood sample collected within one 
week of starting treatment, 4 post-treatment peripheral blood samples collected 
approximately one hour following the completion of both infusions (one on each infusion 
day), and 3 pre-treatment blood samples collected at the time of routine lab collection on 
days 8, 15, and 22.  Fresh whole blood samples will be processed in the laboratory of Dr. 
Jerome Ritz and Biothera will provide the funding necessary to complete this work.  
Using reagants and a flow cytometric protocol provided by Biothera, we will quantify the 
percentage of Imprime PGG-bound and unbound neutrophils following each weekly 
treatment.  Preclinical evaluation of healthy subjects, and cancer patients participating in 
Imprime PGG studies, demonstrate that based on the ability of Imprime PGG to bind to 
neutrophils and monocytes, subjects can be categorized into (i) binders- in which  
Imprime PGG bound to 5% or more of the total neutrophil population and (ii) low or non-
binders- in which Imprime PGG bound to less than 5% of total neutrophils.  We will 
correlate the percentage of Imprime PGG bound neutrophils with treatment response.  
Flow cytometric analysis of pre- and post-treatment changes in neutrophil activation 
marker expression using antibodies against CD11a, CD11b, CD63, CD87 and CBRM1/5 
will also be performed.25  This flow cytometric profile was used to quantify the 
proportion of activated neutrophils in whole blood before and after immunotherapy with 
an anti-tumor monoclonal antibody and GM-CSF in patients with neuroblastoma.  All 
five markers of neutrophil activation were upregulated following treatment, and the 
degree to which they were upregulated correlated with outcome as reflected by 
progression-free survival.  We will use this profile to quantify the proportion of activated 
neutrophils pre- and post-therapy on our study and correlate this with treatment response.    
 
Finally, more recently it has been appreciated that one factor that distinguishes Imprime 
PGG “binders” from “non-binders” is whether a patients has a high level of endogenous 
anti-beta glucan antibodies.  Preliminary clinical data indicate superior clinical response 
to beta-glucan therapy in biomarker positive (i.e. high binder, high anti-beta glucan level) 
patients (internal Biothera data).   To investigate this further, Biothera has developed an 
in-house ELISA assay for the detection and quantification of IgG and IgM antibodies 
against beta glucan.  Pre- and post-treatment serum samples obtained at the timepoints 
outlined above will be shipped to Biothera for analysis of anti-beta glucan antibody 
levels. Exploratory analysis of baseline beta glucan levels and binding capacity, and 
changes during therapy will be assessed and correlated with clinical outcomes. 

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In the event that either funding and/or blood/serum samples are limited, these studies will 
be prioritized as follows: 1) flow cytometric analysis for quantification of Imprime PGG 
bound neutrophils 2) ELISA assay for detection and quantification of anti-beta glucan 
antibodies and 3) flow cytometric analysis for the quantification of activated neutrophils. 
9. STUDY CALENDAR 
Baseline evaluations are to be conducted within 2 weeks prior to the start of protocol 
therapy.  Scans must be done < 6 weeks prior to the start of therapy.  In the event that the 
participant’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. 
All assessments must be performed prior to administration of any study medication.  All 
study assessments and medications should be administered within + 3 days of the 
protocol-specified date, unless otherwise noted. 
The follow-up schedule will be at the discretion of the treating clinician, as long as the 
required study visits (see Table below) are met. 
Study Calendar 
Study 
Assessment 
Baseline
Week 1 
Week 2 
Week 3 
Week 4
Post 
Treatment
6 
Follow-up 
visits (6mo 
and 1 year 
+/- 4 
weeks) 
4 
Study Days 
-14 to -1 
1 
8 
15 
22 
92 
 
Study Drug: 
Imprime PGG 
 
x 
x 
x 
x 
 
 
Rituximab 
 
x 
x 
x 
x 
 
 
Medical 
History, 
Medication 
Review, 
Physical Exam, 
Weight 
x 
x 
x 
x 
x 
x 
X7 
Toxicity 
Assessment 
 
x 
x 
x 
x 
x 
x 

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ECOG 
Performance 
Status1 
x 
x 
x 
x 
x 
x 
x 
ECG 
x 
 
 
 
 
 
 
CBC, 
Differential, 
Blood 
Chemistries2 
x 
x 
x 
x 
x 
x 
x 
Hep B/C 
serology, 
pregnancy 
testing8 
x 
 
 
 
 
 
 
Tumor 
restaging3 
x4 
 
 
 
 
x4 
x4 
Peripheral 
blood collection 
for neutrophil 
studies5 
x5 
x5 
x5 
x5 
x5 
 
 
1Should be obtained at baseline and at the start of every cycle; see Appendix B for 
additional information. 
2Blood chemistries to include complete metabolic panel, LDH. Labs on C1D1 do not 
have to re-meet eligibility other than the ANC must be >1000 as required for all 
treatment days. 
3Tumor restaging will be with CT scans of the chest, abdomen, and pelvis. 
4Tumor restaging should be performed within the 6 weeks prior to 1st administration of 
treatment, and 10 weeks +/- 3 days after week 4 of treatment.  Surveillance during the 
one year +/- 4 weeks follow-up will include CT scans of the chest, abdomen and pelvis 
every 6 months from the end of treatment. 
5 One pretreatment peripheral blood sample(s) will be collected for correlative studies 
(Section 8) within the 1 week prior to the first administration of treatment.  Sampling will 
also be collected 1 hour following the end of both infusions and on each infusion day and 
pre-infusion with routine labs on days 8, 15, and 22 for all of the studies outlined in 
section 8.   
6End of study visit to be performed 10 weeks +/- 3 days after the end of treatment with 
tumor restaging performed at this time. 

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7At follow up visits, only medication review is required. 
 
8Hepatitis B/C serology should include Hep B core, Hep B surface anti-body and antigen, 
Hep C anti-body, Hep B and Hep C viral loads. 
9.1 
Required data 
The following must be obtained within 14 days prior to the 1st day of treatment: 
 Medical history, medication review, physical exam, height and weight, ECOG 
performance status (see Appendix B) 
 CBC with manual differential, blood chemistries including complete metabolic 
panel, LDH, quantitative immunoglobulins and β2-microglobulin 
 Hepatitis B and C serologies 
 Serum or urine β-HCG for females of childbearing potential 
 Electrocardiogram 
 Tumor restaging (within 6 weeks).  This will consist of CT scans of the  chest, 
abdomen, and pelvis. 
 Peripheral blood sample for neutrophil studies (within 1 week prior to the 1st of 
treatment; Section 8) 
 
9.2 
Required data during study 
The following must be obtained during the study: 
 Medical history, medication review, physical exam, and weight, ECOG 
performance status (see Appendix B) 
 Toxicity assessment 
 CBC with manual differential, blood chemistries including complete metabolic 
panel and LDH – day 1 of week 1-4 
 Peripheral blood sample for neutrophil studies 1 hour after treatment on day 1 of 
weeks 1-4 of treatment and serum for evaluation of anti-beta glucan antibody 
levels 
9.3 
Required at post-treatment visit (10 weeks +/- 3 days from end of 
treatment) 
 
The following must be obtained at post-treatment visit (10 weeks+/- 3 days from the last 
day of treatment).  

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 Medical history, medication review, physical exam, height and weight, ECOG 
performance status (see Appendix B) 
 Toxicity assessment 
 CBC with manual differential, blood chemistries including complete metabolic 
panel and LDH 
 Tumor restaging, which will consist of CT scans of the  chest, abdomen, and 
pelvis 
 Surveillance during the  six month and 1 year (+/- 4 weeks) follow-up period 
(from the end of treatment) will include physician visits with routine laboratory 
evaluation, physical exam, and CT scans of the chest, abdomen, and pelvis every 
6 months.  Additional physician visits with routine laboratory assessment and 
physical exam will be left up to the discretion of the treating physician. 
 
10. MEASUREMENT OF EFFECT 
 
Response criteria will follow the International Harmonization Project for Lymphoma 
criteria26 (see Appendix C) using CT scans of the  chest, abdomen, and pelvis. 
 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 Definitions 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical 
condition or experience that develops or worsens in severity after starting 
the first dose of study treatment or any procedure specified in the protocol, 
even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse 
events only if they induce clinical signs or symptoms or require treatment 
or further diagnostic tests.  
11.1.2 Serious adverse event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose 
and regardless of causality that:  
 Results in death 
 Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction which hypothetically might have 
caused death had it occurred in a more severe form. 

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 Requires or prolongs inpatient hospitalization (i.e., the event 
required at least a 24-hour hospitalization or prolonged a 
hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not 
considered SAEs if the illness or disease existed before the person 
was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
 Results in persistent or significant disability/incapacity. Disability 
is defined as a substantial disruption of a person’s ability to 
conduct normal life functions. 
 Is a congenital anomaly or birth defect; or 
 Is an important medical event when, based upon appropriate 
medical judgment, it may jeopardize the participant and require 
medical or surgical intervention to prevent one of the outcomes 
listed above. 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. 
 
 
Events not considered to be serious adverse events are hospitalizations 
for: 
 routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition, or for elective 
procedures 
 elective or pre-planned treatment for a pre-existing condition that 
did not worsen 
 emergency outpatient treatment for an event not fulfilling the 
serious criteria outlined above and not resulting in inpatient 
admission 
 respite care 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
11.1.3.1 
Expected adverse event 
 
Expected adverse events are those that have been previously 
identified as resulting from administration of the agent. For the 
purposes of this study, an adverse event is considered expected 

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when it appears in the current adverse event list, the 
Investigator’s Brochure, the package insert or is included in the 
informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events 
associated with the study agent(s). 
11.1.3.2 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered 
unexpected when it varies in nature, intensity or frequency from 
information provided in the current adverse event list, the 
Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk.   
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse 
event and the study treatment. Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment.  
 Unlikely - The AE is doubtfully related to the study treatment. 
 Unrelated - The AE is clearly NOT related to the study treatment. 
11.2 Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during 
questioning, directly observed, or detected by physical examination, laboratory 
test or other means, will be recorded in the participant’s medical record and on 
the appropriate study-specific case report forms.  
 
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 website 
at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 

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11.3 Reporting Requirements 
 
The study must be conducted in compliance with FDA regulations, local safety 
reporting requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that 
institution to their respective IRB. It is the responsibility of each participating 
investigator to report serious adverse events to the study sponsor and/or others 
as described below.  
11.4 Reporting to the Study Sponsor 
11.4.2 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study 
treatment, during treatment, or within 30 days of the last dose of treatment 
must be reported to the DF/HCC Overall Principal Investigator on the 
local institutional SAE form. This includes events meeting the criteria 
outlined in Section 11.1.2, as well as the following: 
 
 Grade 2 (moderate) and Grade 3 (severe) Events – Only events that 
are unexpected and possibly, probably or definitely 
related/associated with the intervention. 
 
 All Grade 4 (life-threatening or disabling) Events – Unless 
expected AND specifically listed in the protocol as not requiring 
reporting. 
 
 All Grade 5 (fatal) Events – When the participant is enrolled and 
actively participating in the trial OR when the event occurs within 
30 days of the last study intervention.  
 
Note: If the participant is in long term follow up, report the death at 
the time of continuing review.  
 
Participating investigators must report each serious adverse event to the 
DF/HCC Overall Principal Investigator within 24 hours of learning of the 
occurrence. In the event that the participating investigator does not 
become aware of the serious adverse event immediately (e.g., participant 
sought treatment elsewhere), the participating investigator is to report the 
event within 24 hours after learning of it and document the time of his or 
her first awareness of the adverse event. Report serious adverse events by 
telephone, email or facsimile to: 
 
 
 
Caron Jacobson, MD 

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617 582 7591 (phone) 
 
 
cajacobson@partners.org 
 
 
617 632 5168 (fax) 
 
Within the following 24-48 hours, the participating investigator must 
provide follow-up information on the serious adverse event. Follow-up 
information should describe whether the event has resolved or continues, 
if and how the event was treated, and whether the participant will continue 
or discontinue study participation. 
 
To ensure patient safety, every SAE, regardless of suspected causality, 
occurring in the following circumstances must be reported to Biothera 
within 24 hours of learning of its occurrence. 
•After the patient has provided informed consent and until the patient 
has stopped study treatment/participation 
•After protocol-specified procedures begin (e.g. placebo run-in, 
washout period, double-blind treatment) and until at least 28 days after 
the patient has stopped study treatment 
• After the start of any period in which the study protocol interferes 
with the standard medical treatment given to a patient (e.g. treatment 
withdrawal during washout period, change in treatment to a fixed dose 
of concomitant medication) and until at least 28 days after the patient 
has stopped study treatment 
 
Any SAEs experienced after this 28-day period should only be reported to 
Biothera if the investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be 
reported as follow-up to the original episode within 24 hours of the 
investigator receiving the follow-up information.  
 
An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported 
separately as a new event. 
 
Information about all SAEs is collected and recorded on the Med Watch 
3500A Form. The investigator must assess and record the relationship of each 
SAE to each specific study drug, complete the Med Watch Form in English, 
and fax the completed form within 24 hours to Caron Jacobson at 617-632-
3470.  
 
All SAEs will have to be submitted to Apcer to be included in our safety database. 
SAEs need to be transmitted to APCER via email 
to safety.biothera@apcerpharma.com or via fax to +1 (609) 531-0154 
 
 

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11.4.3 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall 
Principal Investigator on the toxicity Case Report Forms.   
11.5 Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly 
to the DFCI Office for Human Research Studies (OHRS). 
 
A copy of the submitted institutional SAE form should be forwarded to: 
 
 
 
Caron Jacobson, MD 
 
 
617 582 7591 (phone) 
 
 
cajacobson@partners.org 
 
 
617 632 5168 (fax) 
 
 
 
11.6 Reporting to the Food and Drug Administration (FDA) 
 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. The DF/HCC Overall 
Principal Investigator will report to the FDA, regardless of the site of 
occurrence, any adverse event that is serious, unexpected and reasonably related 
(i.e., possible, probable, definite) to the study treatment. 
 
Unexpected fatal or life-threatening experiences associated with the use of the 
study treatment will be reported to FDA as soon as possible but in no event later 
than 7 calendar days after initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study 
treatment will be reported to FDA as soon as possible but in no event later than 
15 calendar days after initial receipt of the information. 
 
 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax 
(1-800-FDA-0178) using Form FDA 3500A (Mandatory Reporting Form for 
investigational agents).  Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
 
11.7 
 Reporting to Hospital Risk Management 
 

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Participating investigators will report to their local Risk Management office any 
subject safety reports or sentinel events that require reporting according to 
institutional policy. 
11.8 
 Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are 
encountered from initiation of study intervention, throughout the study, and 
within 28 days of the last study intervention should be followed to their 
resolution, or until the participating investigator assesses them as stable, or the 
participating investigator determines the event to be irreversible, or the 
participant is lost to follow-up. The presence and resolution of AEs and SAEs 
(with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, 
and/or monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, 
consultant report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that 
might reasonably be related to participation in this study. Participating 
investigators should notify the DF/HCC Overall Principal Investigator and their 
respective IRB of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may 
reasonably be related to the study.   
 
12. DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1 Method  
The QACT will collect, manage, and monitor data for this study.  
12.1.2 Data Submission  
The schedule for completion and submission of case report forms (paper or 
electronic) to the QACT is as follows: 

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12. Form 
13. Submission Timeline 
Eligibility Checklist 
Complete prior to registration with 
QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle
Adverse Event Report Form Within 10 days of the last day of the cycle
Response Assessment Form 
Within 10 days of the completion of the 
cycle required for response evaluation 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment 
or being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
 
12.2 Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and 
monitor toxicity and accrual data from this trial. The committee is composed of 
clinical specialists with experience in oncology and who have no direct 
relationship with the study. Information that raises any questions about 
participant safety will be addressed with the Principal Investigator and study 
team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity 
and accrual data.  Information to be provided to the committee may include:  
up-to-date participant accrual; current dose level information; DLT information; 
all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring within 30 days for Phase 1 or 2 protocols; for 
gene transfer protocols, summary of all deaths while being treated and during 
active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) 
will be provided upon request.  
 
 

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12.3 Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by 
representatives designated by the DF/HCC Overall Principal Investigator (or 
Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these 
activities were conducted and data were recorded, analyzed, and accurately 
reported in accordance with the protocol, institutional policy, Good Clinical 
Practice (GCP), and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and 
adherence to protocol requirements. Monitoring will begin at the time of 
participant registration and will continue during protocol performance and 
completion.  
 
13. REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit 
participants) and any other necessary documents must be submitted, reviewed 
and approved by a properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and 
must be approved by the IRB prior to implementation. Any changes in study 
conduct must be reported to the IRB. The DF/HCC Overall Principal 
Investigator (or Protocol Chair) will disseminate protocol amendment 
information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made 
in writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed 
decision about their participation in this study. The formal consent of a 
participant, using the IRB approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The 
consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining 

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the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must 
be retained in the medical record or research file.  
13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, 
which represent good and sound research practice: 
 
US Code of Federal Regulations (CFR) governing clinical study 
conduct and ethical principles that have their origin in the Declaration 
of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical 
Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
 
State laws 
 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-
research-unit-cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except 
when necessary to eliminate an immediate hazard to a research participant. 
In such case, the deviation must be reported to the IRB according to the 
local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and 
the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 

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recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
 
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
 
14. STATISTICAL CONSIDERATIONS 
 
 
14.1 Study Design/Endpoints 
 
This is an open-label, single-arm, phase II clinical trial of Imprime PGG in 
combination with rituximab in patients with relapsed/refractory indolent B cell non-
Hodgkin lymphomas.  The primary endpoint is efficacy as measured by overall 
response rate.  Secondary endpoints will include response duration, progression free 
survival at 1 year, , and rate of grade III and IV adverse events or discontinuation due 
to toxicity.  We will estimate the proportion of patients alive without progression at 
12 months after study entry.  All patients must be followed for a minimum 12 months 
and must have scans at 6 and 12 months.  No patients will be censored for this 
assessment.  The one-year rate of being alive without progression will be estimated as 
a binomial proportion, and an exact binomial 90% confidence interval will be 
provided.  
 
 
Patients will be accrued in a single stage design, with a goal accrual of 25 patients.  
Assuming a 30% response rate with rituximab alone, if the true but unknown rate of CR 
or PR is 50% with the addition of Imprime PGG, the probability of observing 11 or more 
patients with a response is 0.79.  Therefore a study with 25 patients, in which an observed 
response rate of 11/25 (44%) would be considered worthy of further consideration.   
 
We propose correlative studies quantifying Imprime PGG-bound and activated 
neutrophils, comparing both to the number and activation of unbound neutrophils from 
the same patient.  We can examine the association between response to therapy (CR/PR 
vs. SD/Progression as best response).   
 
14.2 Early Stopping- Toxicity 
 
If 3 or more participants experience a grade 4 non-hematologic toxicity, the study will be 
suspended and the data will be reviewed by the data monitoring committee.  

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Additionally, if at any point in the study any participant experiences a grade 5 toxicity, 
the study will be suspended and the toxicity data including attribution will be carefully 
reviewed.  If these toxicity events are determined to be at least possibly related then the 
study will close. 
 
Dr. Caron Jacobson reserves the right to discontinue the study at any time.  
 
14.3 Sample Size/Accrual Rate 
 
The planned sample size is 25 patients.  Based on historical rates, accrual will be 
complete in 24 months.  The total anticipated duration of the study, after the first patient 
is enrolled, will be approximately 36 months. 
 
14.4 Reporting and Exclusions 
 
The primary analysis will be performed on all evaluable patients. 
 
14.5 Disclosures and Confidentiality 
 
The investigator requests strict confidentiality from his/her staff and the IRB.  Study 
documents provided by Biothera (protocols, investigators’ brochures, case report forms, 
and other material) will be stored appropriately to ensure their confidentiality.  The 
information provided by Biothera to the investigator may not be disclosed to others 
without direct written authorization from Biothera, except to the extent necessary to 
obtain informed consent from patients who wish to participate in the trial. 
 
15. PUBLICATION PLAN 
 
The results of this study will be submitted for presentation at national meetings and for 
publication in appropriate journals within 24 months of the completion of the study.  The 
first analysis and submission will be conducted when all patients have reached the End of 
Study visit (or been taken off study). 
 
 

Imprime PGG and rituximab for relapsed indolent NHL 
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16. REFERENCES 
 
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Gavioli R, Spisani S, Giuliani AL, Cosulich E, Risso A, Traniello S. CD16 and 
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generating a primed state of the receptor that mediates cytotoxic activation in 
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Vetvicka V, Thornton BP, Ross GD. Soluble beta-glucan polysaccharide binding 
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11. 
Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and 
cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N 
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Lievre A, Bachet JB, Boige V, et al. KRAS mutations as an independent 
prognostic factor in patients with advanced colorectal cancer treated with 
cetuximab. J Clin Oncol. Jan 20 2008;26(3):374-379. 

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40 
 
13. 
Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit 
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Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-
CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa 
gene. Blood. Feb 1 2002;99(3):754-758. 
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Farag SS, Flinn IW, Modali R, Lehman TA, Young D, Byrd JC. Fc gamma RIIIa 
and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell 
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Golay J, Lazzari M, Facchinetti V, et al. CD20 levels determine the in vitro 
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Cheung IY, Hsu K, Cheung NK. Activation of peripheral-blood granulocytes is 
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17. APPENDICES 
 
17.1 APPENDIX A: HYPERSENSITIVITY ALGORITHM 
 
 
 

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17.2 
 APPENDIX B: PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade
Description
Percent
Description
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease.
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease.
70 
Cares for self, unable to carry on 
normal activity or to do active 
work.
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent.
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20
Very sick, hospitalization 
indicated. Death not imminent. 
10
Moribund, fatal processes 
progressing rapidly.  
5
Dead.
0
Dead.
 
 
 
 
 
 
 

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17.3 APPENDIX C: RESPONSE CRITERIA FOR LYMPHOMA 
 
(adapted from the International Harmonization Project for Lymphoma Criteria26) 
Response
Definition
Nodal masses
Spleen/liver
Bone Marrow
Complete 
Response 
(CR) 
Disappearance of 
all evidence of 
disease 
(a) For FDG-avid or PET 
positive prior to therapy; 
mass of any size permitted 
if PET negative  
(b) For variably FDG-avid 
or PET negative; 
regression to normal size 
on CT
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
 
Partial 
Response 
(PR) 
Regression of 
measurable 
disease 
and no new sites 
≥50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in size 
of other nodes 
(a) FDG-avid or PET 
positive prior to therapy; 
one or more PET positive 
at previously involved site 
(b) Variably FDG-avid or 
PET  negative; regression 
on CT 
≥50% decrease 
in SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
Stable 
Disease 
(SD) 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET 
positive prior to  therapy; 
PET positive at prior sites 
of disease and no new sites 
on CT or PET 
(b) Variably FDG-avid or 
PET negative; no change 
in size of previous lesions 
on CT 
 
 
Relapsed 
or 
Progressive 
Disease 
(PD) 
Any new lesion or 
increase by  ≥50% 
of 
previously 
involved sites 
from nadir 
 
Appearance of a new 
lesion(s)>1.5cm in any 
axis, ≥50% increase in 
SPD of more than one 
node, or ≥50% increase in 
longest diameter of a 
previously identified node 
>1cm in short axis 
Lesions PET positive if 
FDG-avid lymphoma or 
PET positive prior to 
therapy 
>50%  increase 
from nadir in 
the SPD of any 
previous 
lesions 
 
New or recurrent 
involvement 
 

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Abbreviations: PET, positron emission tomography; CT, computed tomography; SPD, sum of the 
product of the diameters.