Clinical trial NCT04081389
Conditions: Anatomic Stage 0 Breast Cancer AJCC v8 Anatomic Stage I Breast Cancer AJCC v8 Anatomic Stage IA Breast Cancer AJCC v8 Anatomic Stage IB Breast Cancer AJCC v8 Anatomic Stage II Breast Cancer AJCC v8 Anatomic Stage IIA Breast Cancer AJCC v8 Anatomic Stage IIB Breast Cancer AJCC v8 Early-Stage Breast Carcinoma Estrogen Receptor Negative HER2/Neu Negative Progesterone Receptor Negative Prognostic Stage 0 Breast Cancer AJCC v8 Prognostic Stage I Breast Cancer AJCC v8 Prognostic Stage IA Breast Cancer AJCC v8 Prognostic Stage IB Breast Cancer AJCC v8 Prognostic Stage II Breast Cancer AJCC v8 Prognostic Stage IIA Breast Cancer AJCC v8 Prognostic Stage IIB Breast Cancer AJCC v8 Triple-Negative Breast Carcinoma
Sponsor: Roswell Park Cancer Institute
Start date: 2019-12-06; Completion date: 2023-02-27
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I trial studies how well chemokine modulation therapy and standard chemotherapy given before surgery work in treating patients with early stage triple negative breast cancer. Chemokine modulation therapy, including celecoxib, recombinant interferon alfa-2b, and rintatolimod, may stimulate the immune system and stop tumor cells from growing. Drugs used in standard chemotherapy, such as paclitaxel, doxorubicin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemokine modulation therapy together with standard chemotherapy may work better than giving either therapy alone in treating patients with triple negative breast cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To examine the safety and tolerability profile of the combination of rintatolimod celecoxib +/- interferon alpha-2b, when given as CKM along with chemotherapy in the neoadjuvant setting in early stage triple negative breast cancer.

II To identify the appropriate dose level of CKM and paclitaxel for future clinical exploration.

SECONDARY OBJECTIVES:

II. • Evaluate the effect of neoadjuvant CKM + paclitaxel on pathological response and breast MRI response in early stage triple negative breast cancer patients.

III. • Evaluate the overall and recurrence-free survival in early stage triple negative breast cancer patients that received neoadjuvant CKM + paclitaxel.

EXPLORATORY OBJECTIVES:

I• To evaluate longitudinal changes of blood biomarkers such as peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), expression of chemokine and other immune genes, circulating immune mediators and correlate them with the clinical course post surgery.

II• Comparison of response assessment criteria for a prospective analysis using RECIST 1.1. and irRECIST

* Evaluate changes in the intratumoral levels of biomarkers, such as, peripheral T-cell subsets, myeloid derived suppressor cells (MDSC), chemokines, and immune-regulatory factors (pre- vs post-CKM + paclitaxel treatment).

OUTLINE: This is a phase Ib, dose-escalation study of recombinant interferon alfa-2b.

Patients receive celecoxib orally (PO) twice daily (BID), recombinant interferon alfa-2b intravenously (IV) over 20 minutes (omitted in lowest dose level), and rintatolimod IV on days 1-3 of weeks 1-3, as well as paclitaxel IV over 1 hour once weekly on day 1. Treatment continues for a total of 12 weeks in the absence of disease progression or unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients receive doxorubicin IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 2 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.

. After completion of study treatment, patients are followed up at 2 weeks.

Arms: arm 1: Patients receive celecoxib PO BID, recombinant interferon alfa-2b IV over 20 minutes, and rintatolimod IV on days 1-3 of weeks 1-3, as well as paclitaxel IV over 1 hour once weekly on day 1. Treatment continues for a total of 12 weeks in the absence of disease progression or unacceptable toxicity. 1-3 weeks after last dose of paclitaxel, patients receive doxorubicin IV over 10 minutes and cyclophosphamide IV over 30 minutes. Treatment repeats every 2 weeks for 4 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Celecoxib intervention 2: Cyclophosphamide intervention 3: Doxorubicin intervention 4: Doxorubicin Hydrochloride intervention 5: Paclitaxel intervention 6: Recombinant Interferon Alfa-2b intervention 7: Rintatolimod
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV intervention 5: Given IV intervention 6: Given IV intervention 7: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Document Coversheet 
 
 Study Title:    Phase I Clinical Trial Assessing the Combination of Chemokine Modulation with 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer    
 
 
Institution/Site:  
Roswell Park Comprehensive Cancer Center 
Document (Approval/Update) Date: 
11/10/2020 
NCT Number: 
NCT04081389 
IRB Number 
I 73718 
 
 


PROTOCOL TITLE: Phase I Clinical Trial Assessing the Combination of Chemokine Modulation 
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PROTOCOL TITLE:  
Phase I Clinical Trial Assessing the Combination of Chemokine Modulation with 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer 
PROTOCOL NUMBER: 
I 73718 
PRINCIPAL INVESTIGATOR: 
Shipra Gandhi, MD 
Roswell Park Comprehensive Cancer Center 
Elm and Carlton Street 
Buffalo, New York 14263 
716-845-1486 
Shipra.Gandhi@roswellpark.org 
PRINCIPAL INVESTIGATOR (GRANT/SCIENTIFIC): 
Pawel Kalinski, MD, PhD 
Roswell Park Comprehensive Cancer Center 
Elm and Carlton Street 
Buffalo, New York 14263 
716-845-7629 
Pawel.Kalinski@roswellpark.org 
VERSION NUMBER: 12 
DATE: 11/05/2020 
Confidentiality Statement 
Any and all information presented in this document shall be treated as confidential and shall 
remain the exclusive property of the party (ies) mentioned above (Roswell Park Cancer Institute 
Corporation d/b/a Roswell Park Comprehensive Cancer Center). The use of such confidential 
information must be restricted to the recipient for the agreed purpose and must not be disclosed, 
published, or otherwise communicated to any unauthorized persons, for any reason, in any form 
whatsoever without the prior written consent of the party(ies) above.
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Table of Contents 
1 
Objectives........................................................................................................................ 3 
2 
Background ..................................................................................................................... 3 
3 
Inclusion and Exclusion Criteria ..................................................................................... 10 
4 
Local and Study-Wide Number of Subjects..................................................................... 12 
5 
Local and Study-Wide Recruitment Methods .................................................................. 12 
6 
Multi-Site Research........................................................................................................ 12 
7 
Study Timelines ............................................................................................................. 12 
8 
Study Endpoints............................................................................................................. 12 
9 
Design ........................................................................................................................... 13 
10 Treatment ...................................................................................................................... 15 
11 Procedures Involved....................................................................................................... 28 
12 Withdrawal of Subjects .................................................................................................. 30 
13 Risks to Subjects ............................................................................................................ 31 
14 Potential Benefits to Subjects ......................................................................................... 34 
15 Data and Specimen Banking ........................................................................................... 34 
16 Measurement of Effect ................................................................................................... 34 
17 Safety Evaluation ........................................................................................................... 35 
18 Data Management and Confidentiality ............................................................................ 40 
19 Statistical Plan ............................................................................................................... 40 
20 Provisions to Monitor the Data to Ensure the Safety of Subjects ...................................... 43 
21 Vulnerable Populations .................................................................................................. 43 
22 Community-Based Participatory Research ...................................................................... 43 
23 Sharing of Results with Subjects..................................................................................... 43 
24 Setting ........................................................................................................................... 43 
25 Provisions to Protect the Privacy Interests of Subjects ..................................................... 43 
26 Resources Available....................................................................................................... 44 
27 Prior Approvals.............................................................................................................. 44 
28 Compensation for Research-Related Injury ..................................................................... 44 
29 Economic Burden to Subjects ......................................................................................... 44 
30 Consent Process ............................................................................................................. 44 
31 Process to Document Consent in Writing ........................................................................ 45 
32 Drugs or Devices ........................................................................................................... 45 
33 REFERENCES .............................................................................................................. 49 
34 APPENDICES/SUPPLEMENTS.................................................................................... 54 
 
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1 
OBJECTIVES 
1.1 
Primary Objective 
• To examine the safety and tolerability profile of the combination of rintatolimod, celecoxib 
± interferon alpha-2b, when given as CKM along with chemotherapy in the neoadjuvant 
setting in early stage triple negative breast cancer 
• To identify the appropriate dose level of CKM and paclitaxel for future clinical exploration. 
1.2 
Secondary Objectives  
• Evaluate the effect of neoadjuvant CKM + paclitaxel on pathological response and breast 
MRI response in early stage triple negative breast cancer patients.  
• Evaluate the overall and recurrence-free survival in early stage triple negative breast cancer 
patients that received neoadjuvant CKM + paclitaxel. 
1.3 
Exploratory Objectives 
• To evaluate longitudinal changes of blood biomarkers such as peripheral T-cell subsets, 
myeloid derived suppressor cells (MDSC), expression of chemokine and other immune 
genes, circulating immune mediators and correlate them with the clinical course post-
surgery. 
• Comparison of response assessment criteria for a prospective analysis using RECIST 1.1. 
(Appendix F) and irRECIST (Appendix G) 
• Evaluate changes in the intratumoral levels of biomarkers, such as, peripheral T-cell 
subsets, myeloid derived suppressor cells (MDSC), chemokines, and immune-regulatory 
factors (pre- vs post-CKM + paclitaxel treatment). 
2 
BACKGROUND 
Breast cancer is one of the leading causes of cancer-related morbidity worldwide (1). 
Approximately 20% of women diagnosed with early breast cancer (EBC) will experience 
recurrence at a distant site within 10 years (2). One key challenge is that breast cancer is a 
heterogeneous disease that is categorized clinically by immunohistochemical (IHC) staining of the 
three receptors: estrogen receptor (ER), progesterone receptor (PR), and the human epidermal 
growth factor receptor-2 (ERBB2/HER2) (3). Seminal studies in the early 2000s demonstrated that 
gene expression signatures could classify breast cancers into distinct and reproducible molecular 
subgroups (4). In essence, breast cancer can be molecularly classified into luminal A and luminal 
B subgroups that are mostly comprised of hormone-receptor positive (HR+) breast cancers; a 
basal-like subgroup that is mostly comprised of triple-negative breast cancers (TNBC); a HER2-
enriched subgroup that is mostly comprised of HER2 + breast cancers and a normal-like subgroup 
that has been proposed to be mostly comprised of the contaminating tumor-surrounding stroma 
(5). 
Triple Negative Breast Cancer 
Triple-negative breast cancer (TNBC) is immunohistochemically defined by the lack of estrogen 
receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2) 
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expression (6). Although it is generally more chemosensitive than other types of breast cancer, it 
is also characterized to harbor the most aggressive behavior with the front-loaded risk of relapse 
within the first 3–5 years after completion of adjuvant chemotherapy and its prevalence in younger 
women (7). Once metastasized, TNBC has a high predisposition to involve the critical visceral 
organs such as lung, liver and brain, eventually leading to a significantly shorter median overall 
survival than in other subtypes (8). Therefore, developing optimal therapeutic strategies for the 
treatment of early TNBC is crucial to alleviate the burden of TNBC. 
Neoadjuvant or adjuvant chemotherapy remains a key component of systemic treatment in early 
TNBC, which is determined primarily by its clinical or pathologic stage (9). Neoadjuvant and 
adjuvant chemotherapy are the standard systemic treatment for early TNBC, and anthracycline and 
taxane-based chemotherapy regimens comprise the current standard of care (10). In previous 
pivotal neoadjuvant trials, patients with TNBC showed significantly higher response rates to 
anthracycline and taxane-based chemotherapy than those of other subtypes. The pathological 
complete response (pCR) observed in triple negative breast cancer after anthracycline and taxane 
based chemotherapy is around 26% (11). Moreover, as pCR showed a significant correlation with 
therapeutic benefits, it has been established as a robust surrogate biomarker for long-term survival 
outcomes (8). Although the guideline for adjuvant chemotherapy is generally similar for each 
breast cancer subtype, adjuvant chemotherapy in TNBC is recommended for primary tumors larger 
than 0.5 cm due to their aggressive behavior (12). Regarding the paradox that TNBC carries both 
higher chemosensitivity and the risk of early relapse, efforts have been continued to develop more 
effective chemotherapeutic regimens for both responders and non-responders. Clinical trials of 
newer combinations and dose-determination studies that evaluated metronomic or dose-dense 
regimens suggested the feasibility of refining conventional chemotherapy (13). 
More recently, patients with an initially high tumor burden or residual disease after neoadjuvant 
chemotherapy were identified as compelling candidates for intensive systemic treatment, as they 
carry higher chance of relapse and metastatic spread. The CREATE-X trial demonstrated the 
potential survival benefit of adding capecitabine to the standard adjuvant chemotherapy regimen 
in early TNBC with a residual tumor burden after neoadjuvant treatment (14). A meta-analysis 
also provided a rationale for adding capecitabine to either neoadjuvant or adjuvant standard 
chemotherapy in patients with TNBC (15). The role of platinum based chemotherapy has also been 
suggested in the neoadjuvant setting in early stage triple negative breast cancer. In the CALGB 
40603 trial (16), the pCR rate was significantly improved from 41% to 54%, in patients who 
received neoadjuvant chemotherapy combining carboplatin and/or bevacizumab with paclitaxel 
followed by dose-dense doxorubicin and cyclophosphamide (ddAC). The GeparSixto trial (17) 
similarly showed significantly enhanced pCR rates from 36.9% to 53.2% by adding carboplatin to 
combinations of ddAC and taxane-based chemotherapy with bevacizumab. In their recent 
secondary analysis, treatment benefit was consistently maintained even in patients without 
BRCA1/2 mutations (18). There has been recent interest in immunotherapy in triple negative 
breast cancer. Due to its genomic instability and high mutational burden, tumour 
microenvironment of TNBC is considered to be ‘hot’ with abundant infiltrating immune cells, 
which are actively engaged in the process of ‘immunoediting’ (19). TILs, mainly the CD8+ T cells, 
are the most famous immune-related player in breast cancer (20). In TNBC treated with 
neoadjuvant treatment, TILs was identified as a robust predictive biomarker of long-term survival 
and its significance in remnant disease was subsequently validated (21) revealing an active 
communication between immune system and cytotoxic agents. Correlation between TILs and 
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programmed cell death 1/ligand 1 (PD-1/PD-L1) expression was suggested in recent experiments, 
which assumed the existence of a feedback loop regulating PD-L1 expression as a means of 
immune homeostasis. Several retrospective studies of early TNBC demonstrated significantly 
worse survival outcomes in patients harboring high PD-L1 expression and a low number of TILs 
or a high ratio of PD-L1/CD8 expression (22). TILs play a significant role in orchestrating the 
immune microenvironment and vigorously interact with cytotoxic signals including both 
chemotherapy and immunotherapy (23). 
Clinical trials have shown the efficacy of immunotherapy in the neoadjuvant setting. In early 
TNBC, preliminary results from the neoadjuvant I-SPY 2 trial demonstrated that pCR rates 
increased from 22.3% to 62.4% by adding neoadjuvant pembrolizumab to paclitaxel followed by 
anthracycline-based chemotherapy, which represents an approximately 40% improvement in pCR 
compared with standard chemotherapy alone (24). The KEYNOTE-173 trial also showed a 
remarkably increased pCR rate from 60% to 90% in high-risk patients by combining 
pembrolizumab with paclitaxel or conventional chemotherapy according to the physician’s 
discretion (25). Since improvement in pathological CR is a surrogate marker for efficacy, hence, 
there is increasing interest in performing clinical trials combining novel agents in the neoadjuvant 
setting in triple negative breast cancer in order to attain a higher pathological complete response. 
2.1 
Pre-clinical Studies with Chemokine Modulation 
The chemokine receptors CXCR3 and CCR5 are typically used by CTLs to enter inflamed tissues. 
High tumor production of CCL5/RANTES (ligand for CCR5) and CXCL9/MIG, CXCL10/IP10, 
and CXCL11/ITAC (three known ligands for CXCR3) is associated with high CTL infiltration in 
different cancer types (26-28). Our previous correlative and mechanistic studies in other cancer 
types (29-31) showed the critical roles of intratumoral production of CCL5, CXCL9, and CXCL10 
in local infiltration with CD8+ GrB+ CTLs, while CCL22 was found responsible for the attraction 
of FOXP3+ Tregs. 
Combinatorial adjuvants: Synergistic and selective induction of CTL-attracting chemokines 
and suppression of Treg attractants: In an attempt to correct the deficit in local production of 
CXCR3 and CCR5 ligands seen in many cancer lesions, we compared the ability of toll like 
receptor (TLR) ligands and cytokines to induce different classes of chemokines. Although TLR3 
ligands, such as poly-I: C were relatively ineffective when used alone and induced a significant 
production of Treg-attracting CCL22 (MDC; CCR4 ligand; Fig. 1), the combination TLR3-L with 
IFNα (and especially with IFNα and COX2 blockers), resulted in a strong synergy in selective 
induction of CXCR3 and CCR5 ligands, with concomitant suppression of CCL22.  
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Figure 1 
 
Studies completed within our NCI-funded program 1P01CA132714 “Directing Tumor-Specific T 
Cells to Tumors” identified TLR3 ligands, poly-I:C (double-stranded RNA; a molecular mimic of 
viral infections and activator TLR3 and RIG-I/MDA5 helicases) and its derivative,  rintatolimod, 
a selective TLR3 ligand, which does not activate helicases and shows improved pattern of TME 
activation, with enhanced safety profile for systemic (i.v.) use, as preferred adjuvants which 
preferentially induce the CTL-/Th1/NK cells-attracting chemokines (29-33) and direct selective 
CTL accumulation in TMEs (29-31).  Furthermore, the combination of rintatolimod (or poly-I: C) 
with IFNα and COX2 blockers (to enhance TLR3 signals and abrogate negative aspects of 
inflammation) are 10- to 100-fold more effective than each of these factors alone in inducing CTL 
attractants, and eliminates Treg attraction (29-31). Such combinatorial chemokine-modulating 
regimen (CKM) acts in tumor-selective fashion, avoiding activation of healthy tissues (29), and 
abrogates the heterogeneity of different tumor lesions (29), converting all “cold” tumors into 
inflamed ones (29-31). 
2.2 
Pre-clinical Studies with Chemokine Modulation and Chemotherapy 
As discussed in the previous section, high tumor production of CCL5, CXCL9, CXCL10, and 
CXCL11 is associated with cytotoxic T-cell infiltration into the different cancer types. Thus, 
intratumoral production of CCL5, CXCL9, and CXCL10 is necessary for infiltration with CD8+ 
cytotoxic T cells, while, CCL22 production is responsible for attraction of FOXP3+ Tregs. 
Treatment of perfused liver tumors with chemotherapy (melphalan) results in production of Treg 
chemokines CCL22 which attracts the T regulatory cells, however, when melanoma models are 
treated ex-vivo with combination of celecoxib, IFN-alpha and poly-I:C, the production of CCL22 
is significantly decreased, hence, supporting the hypothesis that combination of chemokine 
modulation with chemotherapy will result in reversal of the immunosuppressive effects of 
chemotherapy and potentiation of tumor infiltration with cytotoxic T-lymphocytes. 
 
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Figure 2 
 
 
Figure 3 
 
2.3 
Clinical Studies with Chemokine Modulation 
Early data from our clinical trials of CKM in CRC: NCT01545141, i.v.; and ovarian cancer: 
NCT02432378; i.p. demonstrate safety of rintatolimod, administered alone or with IFNα, and local 
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efficacy in the TME of patients receiving systemic or local CKM (chemokines, immune markers, 
Figure 4). 
 
Figure 4 
 
 
Figure 4: Safety and effectiveness of CKM in reprograming of patients’ TME: Upper panel: 
(NCT01545141/UPCI 10-131): Increased ratios of CXCL10 (CTL-attractant) to CCL22 (Treg-
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attractant), and CD8+ /FoxP3 ratios (TaqMan) in resected tumors of CRC patients receiving CKM 
(IFN doses: 5-10-20Million Units/m2, rintatolimod (200mg/d), both.i.v., and oral celecoxib 
(2x200 mg/d), compared with control patients. Bottom Panel: (NCT02432378/UPCI 11-128): 
I.P. increases in CD8, PD1, PDL1 and PDL2 in the first patient receiving i.p. cisplatin, followed 
by rintatolimod (200 mg; lowest cohort, no IFNα). Two patients recently completed the second 
tier of i.p. CKM (rintatolimod + 2MU IFNα) without  DLTs. Clinical trial at RPCI I-52917 of 
chemokine modulation in patients with colorectal cancer metastatic to the liver has enrolled 10 
patients thus far and no DLTs have been observed. No treatment-related grade 3 or 
greater toxicities have been observed. The treatment has been well tolerated overall. 
2.4 
Clinical Studies with Chemokine Modulation and Chemotherapy  
In addition to the evaluation of rintatolimod, interferon alpha-2b and celecoxib administered i.v. 
for one course over 5 days, as a stand-alone treatment, the same combinations (but different 
administration regimens) are being evaluated as a part of combinatorial regimens in additional 
patients with peritoneal carcinomatosis treated with HIPEC (NCT02151448 / UPCI 12-110) and 
recurrent ovarian cancer (NCT02432378 / UPCI 11-128). Clinical trial NCT02151448 (over 50 
de-bulked and HIPEC-pretreated patients evaluated so far) involve multiple cycles of DC vaccines 
followed by 4 day long cycles of IFN- α /celecoxib regimen, with rintatolimod administered on 
days 2 and 4 of each cycle. Clinical trial NCT02432378 (5 patients evaluated so far) involve 
multiple cycles of intraperitoneal (i.p.) chemotherapy followed (with 1 day delay) by single i.p. 
doses of rintatolimod with increasing i.p. doses of IFN-α and a standard dose of celecoxib (orally). 
No DLTs have been observed in any of these trials to date and, the combinations have been 
uniformly well tolerated. 
2.5 
Rationale for Neoadjuvant Chemokine Modulation 
The proposed study will allow for in human proof of concept study which will serve as a basis for 
future combination proposals. 
Currently, neoadjuvant chemotherapy is the standard of care for triple negative breast cancer, with 
pCR of about 30%. CKM will result in production of chemokines which would attract CD8+ T 
cells and decrease production of chemokines which favor immunosuppressive T regulatory cells, 
and hence, result in increased local infiltration of CD8+ T cells and hence, create an immunogenic 
environment as show in Figure 1. We hypothesize that higher number of CD8+ T-cells will result 
in increased efficacy of paclitaxel. Chemokine modulation, which we hypothesize from prior 
preclinical and clinical data, stimulates infiltration of the tumor by T-cells resulting in anti-tumor 
efficacy. Our hypothesis is that the combination will result in higher tumor infiltration with 
cytotoxic T-cells, resulting in an improvement in pCR which is considered a surrogate marker for 
survival. 
2.6 
Planned Correlative Studies 
Tumor tissue, blood and serum samples will be evaluated for evidence of immune modulation and 
anti-cancer activity. Cytokine panel will be compared to pre-treatment samples and we will 
evaluate the T cell circulating component. 
In addition, to identify responders vs. non-responders, we will also perform a biopsy after the 
patient has received 3 doses of CKM + paclitaxel combination therapy. 
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*specimens remaining after analyses on this study may be kept for future research, for patients 
who consented to the optional specimen banking. 
3 
INCLUSION AND EXCLUSION CRITERIA 
3.1 
Inclusion Criteria 
To be included in this study, participants must meet the following criteria: 
1 Age ≥ 18 years of age. 
2 Have pathologically confirmed diagnosis of resectable triple negative breast cancer 
(ASCO/CAP guidelines will be used to define triple negative breast cancer).  
3 Must have measurable disease. Multi-centric disease is allowed. If patient has another 
lesion which is biopsied with ER/PR positive it will be Physician discretion for this 
eligibility criteria 
4 Prior therapy: No prior cytotoxic regimens are allowed for this malignancy. Participants 
may not have had prior chemotherapy, other targeted anticancer therapies, or prior 
radiation therapy to the ipsilateral breast for this malignancy. Prior bis-phosphonate 
therapy is allowed. 
5 Patient eligible for surgery as determined by patient’s surgeon. 
6 Patient must have a lesion amendable to biopsy, unless inaccessible and with PI approval. 
7 Have an ECOG performance status of ≤ 2. Refer to Appendix A. 
8 Participants of child-bearing potential must agree to use adequate contraceptive methods 
(e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should 
a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately. 
9 Ability to swallow and retain oral medication. 
10 Ability to undergo MRI. 
11 Must have adequate organ and marrow function present as defined below: 
o Platelets ≥ 100,000/µL 
o Hemoglobin ≥ 9 g/dL 
o Absolute Neutrophil Count (ANC) ≥ 1500/µL 
o Total bilirubin ≤ institutional upper limit of normal (ULN) 
o AST (SGOT) and ALT (SGPT) ≤ 1.5 X institutional ULN 
o Creatinine < ULN 
OR 
Creatinine clearance ≥ 50 mL/min per Cockcroft-Gault Equation for patients with 
creatinine levels greater than ULN-refer to Appendix D. 
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12 Left Ventricular Ejection Fraction (LVEF) ≥ 55%. If LVEF is <55% and patient is 
otherwise study-eligible, the PI will discuss with cardiologist if patient is eligible to receive 
doxorubicin and participate in study. 
13 Participant or legal representative must understand the investigational nature of this study 
and sign an Independent Ethics Committee/Institutional Review Board approved written 
informed consent form prior to receiving any study related procedure. 
14 Participants on this study will be counseled on and are willing to use adequate 
contraceptive methods.  
Please refer to Appendix B for the Investigator Study Eligibility Verification Form: Inclusion 
Criteria. 
3.2 
Exclusion Criteria 
Participants will be excluded from the study for the following: 
1. Patients currently treated with systemic immunosuppressive agents, including steroids, are 
ineligible until 3 weeks after removal from immunosuppressive treatment. 
2. Patients with active autoimmune disease, requiring ongoing immunosuppressive therapy 
or history of transplantation. 
3. Diagnosis of invasive carcinoma within the last 3 years. 
4. Inflammatory breast cancer will be excluded from the study. 
5. Participants who have metallic surgical implants that are not compatible with an MRI 
machine are not eligible. 
6. Pregnant or nursing female participants. 
7. Unwilling or unable to follow protocol requirements. 
8. Patients with known serious mood disorders (Major depression is an exclusion). Other 
stable mood disorders on stable therapy for > 6 months may be allowed after consultation 
with PI) 
9. Cardiac risk factors including: 
o Patients experiencing cardiac event(s) (acute coronary syndrome, myocardial 
infarction, or ischemia) within 3 months of signing consent 
o Patients with a New York Heart Association classification of III or IV (Appendix 
E) 
10. History of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or upper 
gastrointestinal perforation within the past 3 years. 
11. Prior allergic reaction or hypersensitivity to NSAIDs or any drugs administered on 
protocol. 
12. Any history of allergy to sulfonamides.  
13. Any history of autoimmune hepatitis. 
14. Grade 1 or higher neuropathy. 
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15. Any condition which in the Investigator’s opinion deems the participant an unsuitable 
candidate to receive study drug. 
Please refer to Appendix C for the Investigator Study Eligibility Verification Form: Exclusion 
Criteria. 
3.3 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this study. 
4 
LOCAL AND STUDY-WIDE NUMBER OF SUBJECTS 
A total of 6-24 participants will be enrolled from Roswell Park. During the dose escalation portion 
of the study, a minimum of 6 subjects will be enrolled, but up to 24 patients may be required due 
to the unknown dose-toxicity relationship. Accrual is expected to take up to 2 years. 
5 
LOCAL AND STUDY-WIDE RECRUITMENT METHODS 
Potential participants will be identified and recruited during scheduled visits to Roswell Park. Non-
investigator Roswell Park physicians and community physicians may also refer potential subjects 
to the investigator for evaluation. There will be no “cold calling”. Informed consent will be 
obtained on all subjects by the investigator prior to all study specific procedure (including 
screening procedures). No subject will be entered into this clinical trial without having a signed 
written consent form. 
6 
MULTI-SITE RESEARCH 
Not applicable: This is a single-site study. 
7 
STUDY TIMELINES 
Depending on the patient’s clinical course, active treatment is expected to be approximately 22-27 
weeks. Surgery will occur 3-6 weeks after completion of chemotherapy. An end of treatment visit 
will occur 2 weeks (± 3 days) after surgery and at that point the patient will come off study and be 
followed as per standard of care. Accrual is expected to take up to 2 years. 
8 
STUDY ENDPOINTS 
8.1 
Primary Endpoint 
• To determine the safety and tolerability of CKM: rintatolimod (a selective toll-like 
receptor-3 agonist), celecoxib +/- IFN- α, with paclitaxel as part of standard paclitaxel and 
doxorubicin/cyclophosphamide neoadjuvant therapy in early stage TNBC. Safety and 
toxicity will be assessed using the CTEP NCI Common Terminology Criteria for Adverse 
Events (CTCAE Version 5.0) 
• To identify the appropriate dose level of CKM and paclitaxel for future clinical exploration. 
8.2 
Secondary Endpoints 
• Pathological response 
• Complete breast MRI response after 12 weeks.  
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• Recurrence-free survival (RFS) and overall survival (OS) will also be assessed. RFS is 
defined as local/regional invasive recurrence, invasive ipsilateral breast tumor recurrence, 
distant recurrence, inoperable (meaning no surgery because of progression), and/or death 
from breast cancer (per standard of care according to physician discretion). RFS will be 
calculated from the time of treatment to event. OS is defined by death from breast cancer, 
non-breast cancer, unknown, or any other cause and will be calculated from the time of 
study entry to event.  
8.3 
Exploratory Endpoints 
• To evaluate longitudinal changes of blood biomarkers such as peripheral T-cell subsets, 
myeloid derived suppressor cells (MDSC), expression of chemokine and other immune 
genes and, circulating immune mediators. 
• Correlate each of the above markers and their change over treatment with the clinical 
course of the disease post-surgery. 
• Comparison of response assessment criteria for a prospective analysis using RECIST 1.1. 
(Appendix F) and irRECIST (Appendix G). 
• Comparing the effect of the neoadjuvant treatment (pre vs post-3 doses of CKM + 
paclitaxel treatment) on immune cells [tumor-infiltrating T cell subtypes, Teff/Treg ratios, 
CD11b+ MDSC; the expression of chemokine receptors (CCR2, CCR5, CCR4, CCR6, 
CXCR3, and CXCR4) and immune checkpoint molecules (PD-1, PD-L1/2, VISTA, 
CTLA-4, LAG3 and TIM3)] using RT-PCR, immunofluorescence (IF) and 
immunohistochemistry (IHC); local expression of Teff-attracting chemokines (CCR5, 
CXCL9, CXCL10 and CXCL11) and Treg/MDSC-favoring chemokines (CCL2, CCL22 
and CXCL12) using IF and RT-PCR; RNA assays and microscopy, RT-PCR for COX-2 
expression, IDO, IL-10, arginase and iNOS and, RNA signatures of groups of immune-
regulatory genes that are modulated by the CKM regimen. Similar markers and additional 
soluble and cell-associated mediators may be evaluated in the circulating immune cells and 
in patients’ sera. Exact scope of the above testing depends on available funding. Fresh or 
archival tissue from pre-, post-treatment biopsies and surgery could be used for additional 
correlative studies. The correlative studies would include multispectral IHC/IF analysis of 
the immune cell phenotypes and their activation /exhaustion status as well as gene 
expression based methods (using e.g., RNA seq) to define genes and pathways significantly 
altered upon CKM regiment and  multi-gene signatures of the response and resistance.   
9 
DESIGN 
Depending on the patient’s clinical course, active treatment is expected to be approximately 22-27 
weeks. Based on the I-SPY (investigation of serial studies to predict your therapeutic response 
with imaging and molecular analysis) design where new investigational agents are studied in 
combination with paclitaxel in the neoadjuvant setting, in our study, patients will be treated with 
weekly doses of paclitaxel first.  
In this Phase I study design each eligible patient will receive breast MRI per standard of care. 
Eligible patients will be treated with paclitaxel, TLR3 agonist (rintatolimod) 200 mg IV for days 
1-3 and COX-2 inhibitor (celecoxib) 200 mg oral twice daily for days 1-3 at fixed doses and 
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escalating doses of IFN-α as presented in Table 1. Safety will be monitored closely by the research 
team and the early phase clinical trials committee. At final dose, three patients will be treated for 
confirmation of safety and if deemed safe, this dose would be taken forward for future clinical 
trials to evaluate the efficacy of the combination. Patients will have a baseline biopsy prior to any 
study treatment. On-treatment biopsy (to evaluate the character of the local immune response) will 
be obtained after the combination of CKM + paclitaxel is complete (before week 4), and this will 
be followed by the remaining doses of paclitaxel. Research blood draws will be collected for all 
the patients as discussed in study calendar Appendix J Figure 5. The CKM regimen is expected to 
promote the accumulation of effector immune cells and antigen presenting cells at the sites of the 
chemotherapy-killed or damaged tumor and to promote local and systemic immunization to 
antigens released from the involuting tumor. Breast MRI assessment will be used as a non-invasive 
serial measurement of response during the course of treatment for Dose Level 4.MRI longest 
diameter and volume will be measured at each time point and will be used for early evaluation of 
response. This will be followed by 4 cycles of dose-dense doxorubicin/cyclophosphamide 
treatment every 2 weeks. The current study design to reverse the sequence of chemotherapy is 
based on the I-SPY trial (Investigation of Serial Studies to Predict Your Therapeutic Response 
with Imaging and Molecular Analysis) where novel agents are studied in addition to paclitaxel 
followed by doxorubicin and cyclophosphamide chemotherapy. Surgery will occur 3-6 weeks after 
completion of chemotherapy. Pathological CR is assessed at surgery about 6 months after the 
treatment is initiated. Waiting until each participant’s outcome has been assessed is less than ideal. 
Hence, to obtain earlier information about the response, MRI measurements will be performed 
longitudinally starting at baseline, end of treatment with paclitaxel, and end of anthracycline 
treatment for Dose Level 4. These measurements are not predictive of pCR, but they do correlate 
with it as shown in I-SPY 1. 
Patients will be monitored for dose limiting toxicities (DLTs) throughout the dose –escalation 
portion of the study. Refer to Section 10.5. 
Figure 5 
Study Schema (Dose Escalation) Pre- and post-treatment biopsies and MRI 
at the completion of paclitaxel (MRI only for the patients on Dose Level 4) 
 
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10 TREATMENT 
10.1 Dosing and Administration 
Treatment is intended for an outpatient setting. However, at the investigator’s/physician’s 
discretion, the participant may receive treatment as an inpatient, if deemed necessary. 
10.2 Dose Escalation  
A dose escalation phase will be carried out to assess the safety and tolerability of CKM when given 
in combination with paclitaxel. During the dose escalation phase, subjects will receive paclitaxel 
in combination with CKM (CKM to be given during weeks 1-3), followed by treatment with 
doxorubicin and cyclophosphamide. Refer to Figure 5. 
Escalation will proceed according to the rules described in Section 19.4. 
Dose levels are described in Table 1. 
Table 1 
Dose Levels 
 
CKM Therapy 
 
 
Dose 
Level 
Celecoxib 
Interferon 
alpha-2b 
Rintatolimod 
Paclitaxel 
Number 
of 
Subjects 
1 
(start) 
200 mg orally 
BID on days 1-
3 of weeks 1-3. 
None 
200 mg 
intravenous (IV) 
on days 1-3 of 
weeks 1-3. 
80 mg/m2 IV 
once weekly 
on day 1 
1-6 
2 
200 mg orally 
BID on days 1-
3 of weeks 1-3. 
5 million 
units/m2 IV on 
days 1-3 of 
weeks 1-3. 
200 mg IV on days 
1-3 of weeks 1-3. 
80 mg/m2 IV 
once weekly 
on day 1 
1-6 
3 
200 mg orally 
BID on days 1-
3 of weeks 1-3. 
10 million 
units/m2 IV on 
days 1-3 of 
weeks 1-3. 
200 mg IV on days 
1-3 of weeks 1-3. 
80 mg/m2 IV 
once weekly 
on day 1 
1-6 
4 
200 mg orally 
BID on days 1-
3 of weeks 1-3. 
20 million 
units/m2 IV on 
days 1-3 of 
weeks 1-3. 
200 mg IV on days 
1-3 of weeks 1-3. 
80 mg/m2 IV 
once weekly 
on day 1 
3-6 
10.2.1 Dose Escalation, Paclitaxel + CKM 
On day 1 of weeks 1-3, the patient will receive paclitaxel and CKM therapy on the same day. The 
following medications will be given in this order:  
• Celecoxib: 200 mg orally  
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• Pre-medications 30 minutes prior to paclitaxel: dexamethasone 12 mg IV (if patient 
tolerates the first dose of paclitaxel well, the dose of dexamethasone will be decreased to 
4 mg IV in the subsequent cycles), diphenhydramine 50 mg IV, famotidine 20 mg IV (pre-
meds may be modified according to investigator and institutional practice). 
• Paclitaxel 80 mg/m2 IV infusion over 1 hour (± 10 minutes) 
• Give normal saline 250 mL over 30 minutes. 
• Remainder of CKM regimen (not including morning dose of celecoxib) will start 1 hour 
after paclitaxel infusion is completed. If necessary due to scheduling, patient tolerance, 
etc., the CKM regimen may be started at least 1 but up to 24 hours post paclitaxel infusion. 
o  If CKM is started on the following day, 500 ml normal saline over 60 minutes will 
be given with the pre-medications and celecoxib 200 mg will be repeated twice 
daily again, as patient will not take the evening dose of celecoxib the same day as 
paclitaxel if the patient does not end up receiving the CKM regimen the same day 
as paclitaxel. 
• Pre-meds for CKM: Acetaminophen (Tylenol) 650 mg by mouth x 1 dose; 
Prochlorperazine (Compazine) 10 mg by mouth x 1 dose – administered 30 minutes prior 
to start of interferon alpha-2b. For dose level 1 in which no interferon alpha-2b is given, 
the Acetaminophen and Compazine pre-meds may be omitted. 
• For dose levels 2-4: Interferon alpha-2b (dose according to assigned dose level) IV over 20 
minutes. No Interferon alpha-2 b is given in dose level 1. 
• Rintatolimod: 200 mg IV, initial administration should begin at a slow rate of infusion 
(approximately 20 cc/ hour) and increase to 40 cc/ hour after 30 minutes. Tubing should 
be flushed with 30 to 50 mL of normal saline solution upon completion. Administration 
will be followed by 1 hour of observation and vital signs at 30 and 60 minutes post infusion 
(± 5 minutes). 
• Celecoxib: 200 mg orally to be taken by the patient at home approximately 12 hours 
following the initial dose (if patient does not end up receiving CKM the same day as 
paclitaxel, will need two additional doses of celecoxib the next/subsequent day when 
patient receives CKM regimen). 
On days 2 and 3 of weeks 1-3, the participant will receive CKM therapy according to the dose 
level assigned. The medications will be given in this order: 
• Pretreatment: 500 mL Normal saline over 60 minutes 
• Pre-meds: Acetaminophen (Tylenol) 650 mg by mouth x 1 dose; Prochlorperazine 
(Compazine) 10 mg by mouth x   dose – administered 30 minutes (± 5 minutes) after 
starting pre-treatment hydration. For dose level 1 in which no interferon alpha-2b is given, 
the Acetaminophen and Compazine pre-meds may be omitted. 
• Celecoxib: 200 mg orally, administered along with pre-meds. 
• For dose levels 2-4: Interferon Alpha-2b (dose according to assigned dose level) IV over 
20 minutes. No Interferon alpha-2 b is given in dose level 1. 
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• Rintatolimod: 200 mg IV, initial administration should begin at a slow rate of infusion 
(approximately 20 cc/ hour) and increase to 40 cc/ hour after 30 minutes. Tubing should 
be flushed with 30 to 50 mL of normal saline solution upon completion. Administration 
will be followed by 1 hour of observation and vital signs at 30 and 60 minutes post infusion 
(± 5 minutes). 
• Celecoxib: 200 mg orally to be taken by the patient at home approximately 12 hours 
following the initial dose. 
If day 1 CKM therapy is postponed to day 2, then CKM therapy will be given on days 2-4 of that 
week. 
10.2.2 Dose Escalation, Paclitaxel Monotherapy 
After the patient has completed 3 weeks of CKM + paclitaxel combination therapy, they will 
continue on weekly paclitaxel alone for an additional 9 doses (weeks 4-12). Each week, paclitaxel, 
80 mg/ m2 IV, will be given over 1 hour (± 10 minutes). Patients should be pre-medicated 
30 minutes prior to each paclitaxel dose with dexamethasone 4 mg-12 mg IV (depending on 
patient tolerance of treatment in previous infusions), diphenhydramine 50 mg IV and famotidine 
20 mg IV. Pre-medications may be modified according to the investigator and/or institutional 
practices. If it is determined a patient is no longer deriving benefit from Paclitaxel, the paclitaxel 
may be discontinued and treatment may proceed using AC dosing according to the schedule of 
events.  
Doxorubicin + Cyclophosphamide (AC) 
After completion of the above, the patient will proceed with dose-dense doxorubicin in 
combination with cyclophosphamide every 2 weeks for 4 cycles. The first doxorubicin + 
cyclophosphamide dose will be given 1-3 weeks after last dose of paclitaxel. 
On day 1 of every 2 week cycle, doxorubicin 60 mg/m2 IV push over 10 minutes and 
cyclophosphamide 600 mg/m2 IV over 30 minutes will be given according to institutional 
standards. Patients should be pre-medicated with anti-emetics to prevent nausea and vomiting (per 
institutional standards). 
10.3 Cohort Management 
During the dose escalation phase, cohort management will be performed by the Phase 1 Cohort 
Management Group. 
10.4 Definition of Dose-Limiting Toxicity 
Participants will be monitored for DLTs. The following events will be considered a DLT: 
• The event occurs within 3 weeks following 1st dose of combination CKM + paclitaxel 
therapy and subsequent enrollment for dose-escalation will only proceed after the 3-week 
period has been completed.  
• The toxicity has been determined by the investigator to be possibly, probably or definitely 
related to celecoxib, rintatolimod, interferon-α2b or paclitaxel. 
• Any death not clearly due to the underlying disease or extraneous causes 
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• Moderate toxicity is defined as any other grade 3 or higher adverse event that is not already 
defined as a DLT. 
• If greater than or equal to 2 out of 5 patients experience a treatment delay of > 21 days, the 
study will be suspended and the Roswell Park Data Safety Monitoring Committee will 
review the study and will make recommendations that include but not limited to; (a) 
continuation of the study, (b) modifications to the design (c) or termination of the study. 
Table 2 
DLT Definition 
Toxicity 
Dose Limiting Toxicity 
Hematology 
CTCAE grade 4 neutropenia lasting more than 7 consecutive days 
despite growth factor support  
CTCAE grade 3 thrombocytopenia lasting more than 7 consecutive 
days and grade 4 thrombocytopenia 
≥CTCAE grade 3 thrombocytopenia with bleeding  
CTCAE grade 3 or 4 febrile neutropenia  
CTCAE grade 3 infection with/ without neutropenia  
Cardiac 
Cardiac toxicity ≥ CTCAE grade 2 
Clinical signs of cardiac disease, such as unstable angina or 
myocardial infarction 
Gastro-intestinal 
≥ CTCAE grade 3 vomiting ≥48 hours despite optimal anti-emetic 
therapy 
≥ CTCAE grade 3 diarrhea ≥48 hours despite optimal anti-diarrhea 
treatment 
≥ CTCAE grade 3 mucositis  
Hepato-biliary 
≥ CTCAE grade 2 total bilirubin for more than 7 consecutive days 
≥ CTCAE grade 3 total bilirubin 
≥ CTCAE grade 3 ALT for > 4 consecutive days  
CTCAE grade 4 ALT or AST 
Grade 4 serum alkaline phosphatase >7 consecutive days 
Any AST or ALT >3 x ULN and concurrent total bilirubin > 2 x ULN 
without initial findings of cholestasis (elevated serum alkaline 
phosphatase)  
Renal  
≥ CTCAE grade ≥3 serum creatinine 
Infusion Related 
Reaction 
≥ CTCAE grade 3  
 
Non-hematologic events ≥ CTCAE grade 3, except for the exclusions noted below: 
Any immune-related 
reaction 
≥ CTCAE grade 3 
≥ CTCAE grade 1 fever lasting more than 7 consecutive days 
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Toxicity 
Dose Limiting Toxicity 
Neurological  
≥ CTCAE Grade 3 neurotoxicity  
Exceptions to DLT 
criteria 
Grade 3 alopecia 
< 5 days of CTCAE grade 3 fatigue 
 
 
Dose escalation will proceed according to Section 19.4. 
Participants who do not have a DLT and who do not complete 6 out of 9 doses (CKM) of 
combination treatment (CKM + paclitaxel) will be replaced in the study. If patient does not receive 
≥ 6/9 doses of CKM during the first 3 weeks, or receives a dose modification within the first 3 
weeks, it will be considered a moderate toxicity significant enough to trigger the 3+3 design.  
10.5 Dose Modifications and Treatment Delays 
Day 1 of each CKM dose may be delayed by 1 day for any reason (i.e. patient tolerance, etc.). In 
this instance, CKM doses will be moved to days 2-4 instead of days 1-3. 
For patient tolerance and toxicities, if dose modifications are needed during the DLT period, this 
will be discussed with the study PI and the research team. With the exception of delaying day 1 
of each CKM dose by 1 day, any other dose delays if needed for toxicity management will need 
to be discussed with the study PI and research team. After the DLT period, chemotherapy 
(paclitaxel, doxorubicin or cyclophosphamide) may be dose modified or delayed per physician 
discretion. If toxicities are observed, based on investigator discretion and the common side 
effects of the study drug and standard of care, attribution will be made to the study drug or 
paclitaxel. Dose reductions for study drugs are mentioned in Section 10.5.2. Study drug will be 
dose -reduced first if attribution unclear between study drug and paclitaxel. If study drugs are 
dose-reduced, one drug will be dose reduced first depending on which drug is most likely 
associated with the toxicity. We are considering DLT period as the first 3 weeks during 
treatment. For close monitoring for any toxicities, patients will be seen weekly for physical 
examination thereafter until week 6. As CKM stimulated T cell infiltration, there is a small 
chance for immune related toxicities past the DLT period. The toxicities for all the patients will 
be monitored for additional 3 months after completing the combination treatment with special 
attention to immune related toxicities.  
 If a DLT attributable to CKM causing delay in paclitaxel or AC dosing greater than 21 days or a 
cumulative delay of >28 days while on treatment is noted after the first 3 weeks, patients will be 
permanently discontinued from protocol therapy. Any of the above situations would cause a hold 
to the trial and reassessment of trial continuation.  
10.5.1 Celecoxib Hematologic and Non-Hematologic Toxicities 
Considered to be possibly, probably, or definitely related to celecoxib (interferon alpha-2b and 
rintatolimod will be continued). Celecoxib will be discontinued for any attributable grade ≥3 
toxicity. 
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10.5.2 Interferon Alpha-2b and/or Rintatolimod Hematologic and Non-hematologic 
Toxicities 
Considered to be possibly, probably, or definitely related to interferon alpha-2b and/or 
rintatolimod. 
Any patient with persistently severe or worsening signs or symptoms of neuropsychiatric, 
autoimmune, ischemic, or infectious disorders will be immediately withdrawn from therapy.  
Interferon alpha-2b:  
• If there is a DLT at 5 million units /m2, then the standard 3+3 design will be triggered. If 2 
patients develop DLT, then patients will not receive any interferon further and in that case, 
we will plan to expand to 6 patients with only rintatolimod and celecoxib.  
• Ophthalmologic toxicity grade ≥3: hold interferon alpha-2b dosing until toxicity is resolved 
to ≤ grade 1 or baseline.  
• Hematologic Toxicities 
For Grade 3 toxicity (thrombocytopenia): 
o 1st incidence– if <7 days to resolution: Treatment to continue if toxicity resolves to 
≤ grade 1 or baseline at the lower dose level as proposed in dose-escalation. The 
dose cannot be re-escalated.  
o If > 7 days to resolution: Treatment to continue if toxicity is resolved to ≤ grade 1 
or baseline at the next study visit at the lower dose level as proposed in dose-
escalation. The dose cannot be re-escalated. 
o 2nd incidence:  Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline 
at the next study visit at the second lower dose level [this is possible in case of only 
20 MU/m2 but in case of 10 MU/m2 – at the second incidence of event, the protocol 
therapy will be discontinued]. The dose cannot be re-escalated. 
            For grade 3 anemia: No dose modification needed and treatment can proceed at the same 
dose and schedule with transfusions. For grade 3 neutropenia, administer interferon at the same 
dose with growth factor support.  
 
For Grade 4 toxicity (thrombocytopenia): 
o 1st incidence– If < 7 days to resolution: Treatment to continue if toxicity is resolved 
to ≤ grade 1 or baseline at the next study visit at the lower dose level. The dose 
cannot be re-escalated. 
o 2nd incidence: Discontinue. 
            For grade 4 anemia: No dose modification needed and treatment can proceed at the same 
dose and schedule with blood transfusion. For grade 4 neutropenia, hold until toxicity resolved to 
≤ grade 1 or baseline (growth factor support allowed) and then restart at same dose.   
• Non-Hematologic toxicities 
For Grade 3 toxicity: 
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o 1st episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline at 
the lower dose level as proposed in dose-escalation. The dose cannot be re-
escalated. 
o 2nd episode:  Protocol therapy discontinued.  
For Grade 4 toxicity: Protocol therapy discontinued.  
Rintatolimod: 
• Hematologic Toxicities 
For Grade 3 toxicity (thrombocytopenia): 
o If < 7 days to resolution: Treatment to continue if toxicity is resolved to ≤ grade 1 
or baseline at a dose reduction of 25%. The dose cannot be re-escalated. 
o If > 7 days to resolution: Treatment to continue if toxicity is resolved to ≤ grade 1 
or baseline at the next study visit at a dose reduction of 25%. The dose cannot be 
re-escalated. 
o 2nd incidence: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline 
at the next study visit at a dose reduction of 25%. (total 50% reduction if the dose 
was not re-escalated). The dose cannot be re-escalated. 
            For grade 3 anemia: No dose modification needed and treatment can proceed at the same 
dose with transfusions. For grade 3 neutropenia, administer rintatolimod at the same dose with 
growth factor support.  
 
 
 
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For Grade 4 toxicity (thrombocytopenia): 
o 1st incidence: If < 7 days to resolution: Treatment to continue if toxicity is resolved 
to ≤ grade 1 or baseline at the next study visit at a dose reduction of 25%. The dose 
cannot be re-escalated. 
o If > 7 days to resolution: Discontinue. 
           For grade 4 anemia: No dose modification needed, and treatment can proceed at the same 
dose with blood transfusion. For grade 4 neutropenia, hold until toxicity resolved to ≤ grade 1 or 
baseline (growth factor support allowed) and then restart at same dose.   
 
• Non-Hematologic toxicities: 
For Grade 3 toxicity: 
o 1st episode: Treatment to continue if toxicity is resolved to ≤ grade 1 or baseline) 
at a dose reduction of 25%.  
o 2nd episode: Protocol therapy discontinued.  
For Grade 4 toxicity: 
o Protocol therapy discontinued.   
10.5.3 CKM Toxicity Management 
The toxicity of high dose interferon (20 million units/ m²/d) has been established by Kirkwood et 
al in a number of trials. Most notable was the E1684 trial (34) where high dose interferon 
(20 million units/ m²/d) was administered daily for 5 days x 4 weeks. In that trial (n=143), grade 3 
toxicities were 67%, grade 4 toxicities were 9% (mainly constitutional and neurologic), and there 
were 2 treatment related mortalities (grade 5) due to hepatotoxicity. The proportion of Grade 3 and 
4 toxicities in that trial were 48.2% for constitutional toxicities (defined as ‘worst grade of any 
constitutional toxicity, including fever, chills, flu-like symptoms, fatigue, malaise, and 
diaphoresis), and 66% for non-constitutional toxicities (23.8% for myelosuppression, 13.9% for 
hepatotoxicity, 28% for neurological toxicity). 
While the combination of high dose interferon and rintatolimod may lead to synergistic additive 
side effects, we will monitor subject toxicities for unexpected increases in constitutional 
symptoms, myelosuppression, hepatotoxicity, and neurological toxicity. Moreover, the presence 
of celecoxib may improve the side effect profile. Our strategy is to continuously monitor treatment 
related occurrences of constitutional symptoms (including fever, chills, flu-like symptoms, fatigue, 
malaise, or diaphoresis). 
These are suggestions for specific toxicities and may be modified for institutional guidelines and 
treating physician preference. 
Gastrointestinal Toxicity 
• Nausea and/or vomiting should be controlled with adequate antiemetic therapy. 
Prophylactic antiemetic therapy can be used at the discretion of the investigator/sub-
investigator. Subjects are encouraged to take plenty of oral fluids. 
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• Diarrhea should be managed with appropriate antidiarrheal therapy. Subjects should be 
encouraged to take plenty of oral fluids. If symptoms do not decrease to grade 1 or less 
with adequate antidiarrheal therapy, all protocol drugs should be held until resolved to < 
grade 1. 
Pain/Fever/Chills/ Flu-like Symptoms 
• For chills and/or fever or mild local pain, acetaminophen will be utilized at the discretion 
of the investigator/sub-investigator or designee. NSAIDs will be avoided.  
Note: Any patient developing fever, cough, dyspnea, or other respiratory symptoms should have a 
chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary 
function impairment, the patient should be closely monitored, and, if appropriate, interferon alpha 
treatment should be discontinued. 
While fever may be related to the flu-like syndrome reported commonly in patients treated with 
interferon, other causes of persistent fever should be ruled out. 
Hypersensitivity Reactions 
Caution: Subjects who had a mild to moderate hypersensitivity reaction have been successfully re-
challenged, but careful attention to prophylaxis and bedside monitoring of vital signs is 
recommended. Hypersensitivity reactions to interferon alpha-2b and/or rintatolimod will be 
managed as follows: 
• Mild symptoms (e.g., mild flushing, rash, pruritus): Complete infusion. Supervise at 
bedside. No treatment required. 
• Moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest discomfort): Stop 
infusion. Give intravenous diphenhydramine 50 mg and intravenous famotidine 20 mg. 
Resume infusion after recovery of symptoms at a 66% slower rate, then, if no further 
symptoms, rate can be titrated up every 5-10 min to initial rate until infusion is complete. 
If symptoms recur, at lowest infusion rate stop the infusion and no further interferon alpha-
2b administered on that day. If symptoms recur after the rate has been increased, stop the 
infusion, treat reaction as per institutional guidelines, consider dexamethasone 20 mg IV 
and restart at 66% slower rate (over 1 hour) without up-titration. Future doses pre-treatment 
modifications and rate modification after discussion with the investigator. Record toxicity. 
• Severe life threatening symptoms (e.g., hypotension requiring pressor therapy, 
angioedema, respiratory distress requiring bronchodilation therapy, generalized urticaria): 
Stop infusion. Treat as per institutional guidelines. Subject should be removed from further 
protocol therapy. Report as serious adverse event. 
Ophthalmologic Disorders 
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, 
retinal hemorrhages and cotton wool spots; optic neuritis, papilledema, and serous retinal 
detachment may be induced or aggravated by treatment with interferon alfa-2b or other alpha 
interferons.  
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• All patients should receive an eye examination at baseline. Patients with preexisting 
ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive 
periodic ophthalmologic exams during interferon alpha treatment. 
• Any patient who develops ocular symptoms should receive a prompt and complete eye 
examination. 
10.5.4 Paclitaxel Toxicity Management 
The following are suggestions for specific toxicities and may be modified per institutional 
guidelines and treating physician preference: 
Anaphylaxis/Hypersensitivity: 
Mild symptoms (Grade 1): mild flushing, rash, pruritus. 
• Complete infusion, observation in treatment area. No treatment required. 
Moderate symptoms (Grade 2): moderate rash, flushing, mild dyspnea, chest discomfort. 
• Stop infusion. 
• Give intravenous diphenhydramine 25 mg and intravenous dexamethasone 10 mg. 
Methylprednisolone (60 mg IV) may be used instead of dexamethasone. 
• Resume paclitaxel infusion after recovery of symptoms, at a slower rate. 10 mL/hour for 
15 minutes, then 25 mL/hour for 15 minutes, then, if no further symptoms, at full dose rate 
until infusion is complete. 
• If moderate or severe symptoms recur after rechallenge, stop paclitaxel infusion, and report 
as an adverse event. 
• Patient may be rechallenged after premedication with dexamethasone 8 mg po or IV q 6 hrs 
x 4 doses (moderate symptoms) or 20 mg po or IV q 6 hrs x 4 doses (severe symptoms) 
and diphenhydramine 25 mg po or IV q 6 hrs x 4 doses (moderate or severe symptoms). 
Methylprednisolone (60 mg IV) may be used instead of dexamethasone. 
• The paclitaxel should be administered at a slower rate. 10 mL/hour for 15 minutes, then 
25 mL/hour for 15 minutes, then, if no further symptoms, at full dose rate until infusion is 
complete. 
Severe life-threatening symptoms (Grade ≥ 3): hypotension requiring pressor therapy, 
angioedema, respiratory distress requiring bronchodilation therapy, generalized urticaria. 
• Stop paclitaxel infusion. 
• Give intravenous diphenhydramine 25 mg and intravenous dexamethasone 10 mg. 
Methylprednisolone (60 mg IV) may be used instead of dexamethasone. 
• Add epinephrine or bronchodilators if indicated. 
• Report episode as an adverse event. 
• Patient will not be re-challenged and will be removed from the study.  
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Cardiac Arrhythmias 
• Asymptomatic, EKG-documented arrhythmias: 
o Stop paclitaxel, and manage arrhythmia according to standard practice. 
o Protocol treatment will be discontinued and the episode reported as an adverse 
event. 
• Asymptomatic sinus bradycardia or tachycardia: 
o No intervention is necessary. 
• Sinus bradycardia or tachycardia associated with hypersensitivity reaction: 
o Please see above. 
Hematologic Toxicity 
If ANC<800 prior to paclitaxel dose 
• Delay paclitaxel (consider growth factor support per standard of care). 
• Check counts weekly until ANC ≥ 800 mm3 
• If a delay of greater than 21 days is required, permanently discontinue protocol therapy and 
notify study chair. 
If platelets < 100,000 prior to paclitaxel dose 
• Dose-modifications per physician discretion. 
Neurologic Toxicity: Neuropathy (motor and sensory) 
Grade 1 or 2 Neurotoxicity: 
• There will be no dose modifications for grade 1 or 2 neurotoxicity. 
• Treatment does not need to be delayed and previously administered doses can be continued. 
• If the patient is experiencing significant distress from grade 2 toxicity or the treating 
physician is uncomfortable with continuing the same doses, a dose reduction of 10 mg/m2 
in the paclitaxel dose is acceptable. 
Grade 3 Neurotoxicity: 
• Patient should not receive additional treatment until the toxicity has resolved to ≤ Grade 2. 
• The next infusion may be delayed up to 2 weeks to allow for neurologic toxicity to improve. 
• If it does not resolve to ≤ Grade 2 after 2 weeks, the patient will be permanently 
discontinued from protocol therapy. 
• Re-treatment should be initiated with a dose of paclitaxel 10 mg/m2 below the previous 
dose level when the toxicity resolves to Grade 2 or less. All subsequent infusions will be 
administered using the reduced dose. 
• If Grade 3 neurotoxicity develops with additional infusions, further dose reductions may 
be made in increments of 10 mg/m2 to a maximum of 4 dose level reductions. 
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• Patients whose toxicity does not improve after 4 dose level reductions will be permanently 
discontinued from protocol therapy. 
• Patients who develop worsening neurotoxicity with each infusion, even if it remains Grade 
2, should be carefully evaluated to determine if a dose reduction would be appropriate. 
• Dose reductions for neurotoxicity: 
o Full dose: 80 mg/m2 
o 1st dose reduction: 70 mg/m2 
o 2nd dose reduction: 60 mg/m2 
o 3rd dose reduction: 50 mg/m2 
o 4th dose reduction: 40 mg/m2 
Grade 4 Neurotoxicity: 
• Permanently discontinued from the study. 
Gastrointestinal Toxicity: 
• Nausea/Vomiting 
o Grade 0-2 Nausea/Vomiting: No change. 
o ≥Grade 3 despite maximal anti-emetic therapy: Hold paclitaxel until ≤Grade 2 then 
restart with 20% dose reduction in subsequent cycles. 
o If nausea/ vomiting toxicity causes a dosing delay of > 21 days, or if ≥Grade 3 
nausea/ vomiting recurs despite dose reduction, permanently discontinue protocol 
therapy and notify study chair. 
Prophylactic antiemetics should be used at the discretion of the investigator. The specific regimen 
must be recorded in the patient’s medical record. 
• Mucositis 
o Grade 2 Mucositis: 
 If Grade 2 mucositis is present on the day of any treatment, the treatment 
should be delayed until the mucositis has resolved to a Grade 1 or 0, and 
then resume paclitaxel at 80 mg/m2. 
o Grade 3 or 4 Mucositis: 
 Delay treatment until mucositis has resolved to Grade 1 or 0 then the dose 
of paclitaxel should be reduced to 70 mg/m2. 
• If Grade 3 or 4 mucositis recurs, treatment should be delayed until 
mucositis has resolved to Grade 1 or 0, and the dose of paclitaxel 
should be reduced to 60 mg/m2. 
• If mucositis causes a delay of > 21 days, the patient should be 
permanently discontinued from protocol therapy. 
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• Once the paclitaxel dose has been decreased, it should not be re-
escalated. 
• Diarrhea 
o Grade 2: 
 If Grade 2 diarrhea is present on the day of any treatment, the treatment 
should be delayed until the diarrhea has resolved to Grade 1 or 0, and then 
resume paclitaxel at 80 mg/m2. 
• If diarrhea causes a delay of > 21 days, the patient should be 
permanently discontinued from protocol therapy. 
 Optimal use of anti-diarrheal agents is encouraged. 
o Grade 3 or 4: 
 If Grade 3 or 4 diarrhea occurs, delay treatment until the diarrhea has 
resolved to grade 1 or 0, then the dose of paclitaxel should be reduced to 
70 mg/m2. 
 If Grade 3 or 4 diarrhea recurs, treatment should be delayed until diarrhea 
has resolved to grade 1 or 0, and the dose of paclitaxel should be reduced to 
60 mg/m2. 
 If diarrhea causes a delay of > 21 days, the patient should be permanently 
discontinued from protocol therapy. 
 Once the paclitaxel dose has been decreased, it should not be re-escalated. 
 Optimal use of anti-diarrheal agents is encouraged. 
• Hepatic Dysfunction 
Because the plasma clearance of paclitaxel is reduced in patients with hepatic impairment; careful 
evaluation of liver enzymes in necessary before the administration of each new cycle of paclitaxel. 
For elevations in total bilirubin, SGOT (AST), SGPT (ALT), the following dose modifications 
will be applied: 
o Grade 1: 
 No dose modifications. 
o Grade 2: 
  Hold paclitaxel for one week. 
 If abnormal tests return to grade 0 or 1, paclitaxel should be continued at 
full dose. 
• If the abnormal test does not return to grade 0 or 1 in one week, but 
remains at Grade 2, continue paclitaxel at 70 mg/m2. If the abnormal 
test result returns to Grade 0 or 1, return to full dose, 80 mg/m2. 
o Grade 3 or 4: 
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 Patient should be permanently discontinued from protocol therapy. 
• Febrile Neutropenia 
Fever ≥38°C (101.3°F) in the presence of neutropenia (ANC <1000): 
• Paclitaxel should be held for all instances of febrile neutropenia. 
o First episode: G-CSF or GM-CSF may be used for subsequent cycles at the 
discretion of the treating physician, but it is not required. There will be no dose 
reduction for the first episode of febrile neutropenia. 
o -Second episode: Remaining doses will be reduced to paclitaxel 70 mg/m2 given 
with G-CSF or GM-CSF. 
o -Three episodes: Remaining doses will be reduced to paclitaxel 60 mg/m2 given 
with G-CSF or GM-CSF. 
o -More than three episodes: Discontinue protocol therapy. 
10.6 General Concomitant Medication and Supportive Care 
Additional cancer directed chemo-, immune-, and radiotherapies are not permitted during the 
active treatment period of this trial. Any supportive care deemed necessary by the investigator (i.e. 
blood transfusions, anti-emetics, etc.) are allowed. Growth factor support may be given as standard 
of care. 
10.7 Compliance 
On days that CKM regimen is given, the morning dose of celecoxib will be administered in the 
Clinical Research Center (or other clinical area) and documented by the nurse on the Medication 
Administration Record. The evening dose of celecoxib will be self-administered at home and 
documented by the participant on the patient diary. The participant will be asked to bring the diary 
with him/her to each clinical visit. 
11 PROCEDURES INVOLVED 
The study-specific assessments are outlined in Study Calendar (Appendix J). 
Unless otherwise defined in the written protocol text, all procedures/assessments will be conducted 
in accordance with Roswell Park Clinical Research Services Standard Operating Procedures. 
Eligibility of each participant will be established prior to start of treatment. 
Informed consent MUST be completed prior to receiving any study related procedures. 
11.1 Correlative Studies 
Blood samples (60 cc) will be collected at the time points specified on the study calendar 
(Appendix J). At each time point, (1) 10 mL red top tube and (5) 10 mL sodium heparin green top 
tubes will be collected. Collection tubes are to be labeled with the participant’s MR number, 
participant’s initials, participant’s study number, time of collection, and protocol day. Specimens 
will be sent at room temperature to the attention of the Correlative Science Pathology Office 
(Pneumatic Station 19) where they will get accessioned for tracking in the source document. Once 
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specimen receipt has been documented, the specimens will be sent at ambient temperature to 
pneumatic station 641 (located in CCC LOB-4th floor). The Kalinski Laboratory will be notified 
via telephone and e-mail (all contacts to be copied with each e-mail-see contact information below) 
prior to sample shipment and, the samples will be held in CSPO until a response is received 
acknowledging that personnel are available to procure the samples from the pneumatic tube 
station. Samples will be processed in the Kalinski Laboratory for future analysis. 
Roswell Park Comprehensive Cancer Center 
Kalinski Laboratory 
CCC Bldg. 5th Floor, Rm. 502F 
Attn: Study Number – I 73718 
Elm & Carlton Streets 
Buffalo, NY 14263 
Tel: 716-845-1300 ext. 7353 
melissa.grimm@roswellpark.org 
Weijian.Jiang@RoswellPark.org 
Per.Basse@RoswellPark.org 
Pawel.Kalinski@roswellpark.org 
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples. 
11.2 Pathology 
11.2.1 Fresh Biopsies 
As per amendment 10, a fresh biopsy is required at baseline for all patients (standard of care). An 
additional biopsy to assess the intratumoral biomarkers will be required for the patients: 
After completion of 3 doses of CKM + paclitaxel combination therapy patients will have fresh 
biopsy collected (prior to 4th dose). 
If patients develop disease progression during the DLT period, tumor biopsy can be performed (if 
patient agrees, not mandatory) and will be analyzed for exploratory endpoints as discussed but will 
not be considered for efficacy analysis as these patients have already developed disease 
progression on treatment.  
4 tumor and 2 surrounding tissue cores will be obtained at each time point. 1 tumor core will be 
fixed in formalin for 8 to 24 hours and processed as a paraffin embedded block (FFPE block). 
Upon completion of processing, the FFPE block will be QC’d and stored ambient at the Correlative 
Sciences Pathology Office (GBSB S-636) until requested. The rest of the core biopsy samples will 
be placed in separate 10-mL cold sterile DPBS (supplied by the Kalinski lab). Label the samples 
as “tumor” or “non-tumor” with study-specific subject ID number, clinical study number, protocol 
time point, and protocol day. Samples will be sent to Dr. Pawel Kalinski’s lab via pneumatic tube 
station #641 (located in CCC-LOB 4th floor) upon completion of processing (preferably ASAP 
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within 2 hours of collection, but within 4 hours of collection is allowed). In case of any delays, the 
samples should be refrigerated (4° C) or kept on ice, but not frozen. 
Roswell Park Comprehensive Cancer Center 
Kalinski Laboratory 
CCC Bldg. 5th Floor, Rm. 502F 
Attn: Study Number – I 73718 
Elm & Carlton Streets 
Buffalo, NY 14263 
Tel: 716-845-1300 ext. 7353 
melissa.grimm@roswellpark.org 
Weijian.Jiang@RoswellPark.org 
Per.Basse@RoswellPark.org 
Pawel.Kalinski@roswellpark.org 
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. 
The Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process 
in place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples. 
12 WITHDRAWAL OF SUBJECTS 
12.1 Treatment Discontinuation 
Upon treatment discontinuation, all end of treatment evaluations and tests will be conducted. The 
reason for treatment discontinuation will be documented in the electronic case report form (eCRF). 
All participants who discontinue due to an AE must be followed until the event resolves or 
stabilizes. Appropriate medical care should be provided until signs and symptoms have abated, 
stabilized, or until abnormal laboratory findings have returned to acceptable or pre-study limits. 
The final status of the AE will be reported in the participant’s medical records and the appropriate 
eCRF. 
Reasons for treatment discontinuation should be classified as follows: 
• Death 
• Toxicity; treatment related or unrelated 
• Investigator judgment 
o The Investigator may discontinue a participant if, in his/her judgment, it is in the 
best interest of the participant to do so. 
• Noncompliance 
• Participant voluntary withdrawal 
o A participant may withdraw from the study at any time, for any reason. If a 
participant discontinues treatment, an attempt should be made to obtain information 
regarding the reason for withdrawal. 
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• Sponsor (Roswell Park) decision.  
13 RISKS TO SUBJECTS 
13.1 Paclitaxel 
Common adverse events: alopecia; diarrhea; inflammatory disease of mucous membrane, nausea 
and vomiting; anemia; leukopenia; neutropenia; thrombocytopenia; hypersensitivity reaction; 
arthralgia; myalgia; peripheral neuropathy. 
Serious adverse effects include: Atrial fibrillation; cardiac dysrhythmia; cardiotoxicity; congestive 
heart failure; myocardial infarction; supraventricular tachycardia; Stevens-Johnson syndrome; 
Toxic epidermal necrolysis, gastrointestinal perforation; Grade 3 or higher nausea and vomiting, 
Grade 3 or higher anemia; deep vein thrombosis; febrile neutropenia; Grade 4 neutropenia; Grade 
3 or greater thrombocytopenia; anaphylaxis; opportunistic infection; sepsis; Grade 3 or higher 
peripheral neuropathy; seizure; tonic-clonic seizure; pulmonary embolism; respiratory failure. 
Paclitaxel is commercially available. Please refer to the package insert for a complete list of 
adverse effects. 
13.2 Doxorubicin 
Common adverse effects: alopecia; nausea; vomiting. 
Serious adverse effects include: cardiomyopathy; congestive heart failure, late onset; left 
ventricular failure, acute; myocardial infarction; pericarditis; tachyarrhythmia, injection site 
extravasation, radiation recall syndrome, tissue necrosis, pancreatitis, acute myeloid leukemia, 
Grade 3 or 4 leukopenia, myelodysplastic syndrome, myelosuppression, neutropenia, Grade 3 or 
4 thrombocytopenia, hepatitis, Veno-occlusive disease of the liver, anaphylaxis, septic shock, 
radiation pneumonitis, tumor lysis syndrome. 
Doxorubicin is commercially available. Please refer to the package insert for a complete list of 
adverse effects. 
13.3 Cyclophosphamide 
Common adverse effects: alopecia; disorder of skin pigmentation; nail damage; rash; abdominal 
discomfort; diarrhea; loss of appetite; nausea and vomiting; leukopenia; neutropenia; amenorrhea. 
Serious adverse effects include: cardiac tamponade; cardiotoxicity; congestive heart failure; 
pericardial effusion; erythema multiforme; malignant tumor of dermis; Stevens-Johnson 
syndrome; Toxic epidermal necrolysis; Acute myeloid leukemia; chronic myeloid leukemia; 
malignant tumor of lymphoid hemopoietic and related tissue; myelodysplastic syndrome, 
angiosarcoma of liver; anaphylaxis; acquired contracture of bladder neck; bladder cancer; fibrosis 
of urinary bladder; hemorrhagic cystitis; pyelitis; renal hematuria; secondary malignant neoplasm 
of renal pelvis; azoospermia; oligozoospermia; interstitial pneumonia; pulmonary fibrosis; 
infectious disease. 
Cyclophosphamide is commercially available. Please refer to the package insert for a complete list 
of adverse effects. 
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13.4 Celecoxib 
Prolonged use of celecoxib may cause dyspepsia, headaches (including migraines) and borderline 
elevated liver function tests (which could indicate liver damage). Recently, information from three 
long-term studies of celecoxib has become available. In the first study, a cancer prevention study, 
an increased risk of heart attacks, strokes, and/or deaths resulting from heart or blood vessel disease 
was reported among people taking celecoxib. Approximately 1 in 100 subjects enrolled in this 
study receiving the placebo treatment had one of these serious events. In contrast, between 2 and 
3 in 100 subjects taking celecoxib (between 400 and 800 mg daily) had one of these serious events. 
Another clinical cancer prevention study found no increased risks in subjects taking celecoxib 
400 mg daily. The third study, an Alzheimer's disease prevention study, did not find increased 
risks with celecoxib. Dosing has been suspended in all three of these studies based on the findings 
of the first cancer prevention study. As a result, the FDA is now evaluating the possibility that 
celecoxib increases the risk of heart attack, stroke, and or death resulting from heart or blood vessel 
disease. Known infrequent side effects of celecoxib include nausea and/or vomiting, diarrhea, 
flatulence, abdominal and stomach pain, bleeding ulcer, upper respiratory tract infection, 
pharyngitis, rhinitis, sinusitis, peripheral edema, back pain, dizziness, insomnia, and skin rash. 
Rare risks include sudden death (unexpected or instant death that occurs within minutes or hours 
from any cause other than violence), vasculitis, hepatitis, liver failure, kidney failure, blood 
dyscrasia, hypoglycemia, hyponatremia, viral meningitis, severe allergic reaction, visual changes, 
and transient ischemic attack. Warnings/Precautions: Stomach problems may be more likely to 
occur if patients drink alcoholic beverages while taking this medicine. Taking two or more of the 
nonsteroidal anti-inflammatory drugs together on a regular basis may increase the chance of 
unwanted effects. Also, taking acetaminophen, aspirin or other salicylates, or ketorolac (e.g., 
Toradol) regularly while taking a nonsteroidal anti-inflammatory drug may increase the chance of 
unwanted effects. The risk will depend on how much of each medicine is taken every day and how 
long the medicines are taken together. Therefore, patients should not take acetaminophen or aspirin 
or other salicylates or ketorolac (e.g., Toradol). Clinical studies with celecoxib have identified 
potentially significant interactions with fluconazole and lithium. Experience with nonsteroidal 
anti-inflammatory drugs (NSAIDs) suggests the potential for interactions with furosemide and 
ACE inhibitors. Celecoxib is contraindicated in patients with known hypersensitivity to celecoxib. 
Celecoxib should not be given to patients who have demonstrated allergic-type reactions to 
sulfonamides. Celecoxib should not be given to patients who have experienced asthma, urticaria, 
or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-
like reactions to NSAIDs have been reported in such patients. 
For more risk information reference the Investigator’s Brochure or package insert. 
13.5 Interferon-α2b 
Interferon alpha-2b may cause fever, chills and flu-like symptoms; loss of appetite; nausea; 
vomiting, diarrhea and abdominal pain; fatigue; lowered white blood count may increase risk of 
infection; lowered platelets may lead to an increase in bruising or bleeding; hair loss. Other risks 
which may be common in cases of prolonged administration of interferon alpha-2b include 
drowsiness; temporary confusion; anxiety, amnesia, irritability, confusion, delusions and 
depression which can be severe; numbness and/or tingling in the hands and/or feet, skin rashes and 
inflammation of the pancreas. Inflammation of the pancreas is swelling or irritation of the pancreas 
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which may result in tenderness or pain in the stomach and/or back. When the pancreas is inflamed, 
the body is not able to absorb all the nutrients it needs. 
For more risk information reference the Investigator’s Brochure or package insert. 
13.6 Rintatolimod 
Clinical experience with rintatolimod totals over 800 patients with more than 400 patients 
receiving rintatolimod for at least six (6) months, greater than 200 patients for one (1) year, over 
50 patients up to two (2) years, and with 20 or more patients over two (2) years at doses as high as 
1200 mg i.v. twice weekly. No evidence of dose-limiting organ toxicity, including hematologic, 
liver, or renal toxicity, has been observed. 
Adverse events related to infusion such as mild flu-like symptoms, transient headache, fever, 
myalgia, arthralgia, and fatigue/malaise which were seen, usually occur during the initial weeks of 
treatment and tend to subside on repeated administration. These side events were seen in Chronic 
Fatigue Syndrome patients, cancer patients, chronic hepatitis B infected patients and individuals 
infected with HIV at doses of 200 and 400 mg and higher. Patients that experience these minor 
side effects can continue on rintatolimod and as noted, these signs and symptoms typically subside 
after several weeks of continued treatment. Specific symptoms of note include a flushing reaction, 
characterized by at least one occurrence of erythema of the face, neck and chest, which has been 
observed in approximately 10% of patients treated in various studies. Usually the flushing is both 
mild and transient and disappears with repeated dosing. Occasionally, it can be accompanied by a 
tightness of the chest, tachycardia, anxiety, shortness of breath, subjective reports of "feeling hot", 
diaphoresis and nausea. The reaction is usually infusion-rate dependent and may generally be 
controlled by slowing the infusion rate. An antihistamine (diphenhydramine hydrochloride) can 
be helpful in controlling and reducing the response in the occasional patient for whom the symptom 
persists. Other less frequently occurring adverse effects include nausea, diarrhea, itching, urticaria, 
bronchospasm, transient hypotension, photophobia, rash, bradycardia and transient visual 
disturbances. A severe unexpected local reaction to extravasation of rintatolimod (Ampligen®, 
Poly I: Poly C12U) at the infusion site in the dorsum of the left hand was reported in a Chronic 
Fatigue Syndrome patient with chilblains. Several patients experienced liver enzyme level 
elevations while receiving rintatolimod associated with chronic dosing over many weeks. 
Rintatolimod has been dosed in combination with alpha interferon in investigator initiated studies 
under investigator IND applications during the period between December 1985 and April 1994. A 
total of 24 patients received combination treatments. Clinical conditions included renal cell 
carcinoma, chronic myelogenous leukemia, melanoma, and ovarian cancer. Rintatolimod was 
given as an IV infusion at a dose of 300 mg twice weekly. The starting dose was sometimes as low 
as 1-10 mg. The interferons were administered at a dose of 3 million units daily, with some doses 
of 0.75 million units at the low side and up to 6 million units at the higher side. 
The therapy with rintatolimod in combination with alpha interferon was generally well tolerated 
without evidence of dose-limiting or cumulative toxicities. The most frequent adverse reactions 
were considered minor in severity and duration. Most of them were flu-like symptoms such as 
chills, cold feeling, fatigue, decreased appetite, fever, muscular aches. Also shortness of breath has 
been seen as well as hypotension, nausea, anemia, dyspnea, numbness, itching and blurred vision. 
These adverse events were judged possibly related to the condition of the patients, but also possibly 
related to the administration of rintatolimod or interferon. In some cases worsening of the patient’s 
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condition has been seen due to tumor progression, but in general favorable clinical patterns were 
observed in these patients with advanced disease. Such combinations were not intended to be 
immune modulating and were evaluated in the context of clinical cancer care. 
For more risk information reference the Investigator’s Brochure or package insert. 
14 POTENTIAL BENEFITS TO SUBJECTS 
Our hypothesis is that CKM in addition to chemotherapy will potentiate the anti-tumor activity of 
the latter and result in a higher pathological complete response. By conducting a biopsy at the end 
of 3 doses of CKM + paclitaxel combination therapy, we will be able to identify early responders 
vs. non-responders (and correlate these findings with the final pathology at the time of surgery). 
15 DATA AND SPECIMEN BANKING 
All samples for correlative analysis will be sent to Dr. Kalinski’s Laboratory for processing (CCC-
502F). Samples will be used for planned study assays as well as for future analysis for other yet to 
be identified biomarkers that may be related to the clinical outcome of the study population. Any 
clinical data that is associated with the samples, will be stored on a secure server in the Department 
of Medicine, will be accessible only by the PI, Co-Investigators and PI designated data manager 
and, will be password protected. All computer entry and networking programs will be done using 
PIDs only. Any clinical data and/or specimens that are used for future studies will be de-identified 
before being released. 
Note: All investigator or analyzing research laboratories housing research samples need to 
maintain current Temperature Logs and study-specific Sample Tracking and Shipping Logs. The 
Principal Investigator/Laboratory Manager must ensure that the stated lab(s) have a process in 
place to document the receipt/processing/storage/shipping of study-related samples/specimens. 
This is required for both observational and interventional clinical studies collecting clinical 
samples. 
16 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 
For the purposes of this study, patients should be re-evaluated by MRI for response at the following 
time points: 
• Prior to start of doxorubicin and cyclophosphamide combination, after completion of last 
paclitaxel treatment (MRI at the completion of paclitaxel only for patients at Dose Level 
4). 
• Prior to surgery, after completion of last dose of doxorubicin/cyclophosphamide 
 
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16.1 Continuation of Treatment Post-Disease Progression 
Progressive disease: If there is evidence of disease progression per RECIST v1.1 but it is 
determined the patient is receiving clinical benefit while on the trial, the patient may continue at 
the discretion of the Principal Investigator. 
17 SAFETY EVALUATION 
17.1 Adverse Events 
An adverse event or adverse experience (AE) is any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of ‘unrelated’, ‘unlikely’, 
‘possible’, ‘probable’, or ‘definite’). 
An AE is considered “unexpected” if it is not listed in the investigator brochure or is not listed at 
the specificity or severity that has been observed; or if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
in other study-related documents. 
• Diagnosis Versus Signs and Symptoms 
If known, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
clinically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded as an AE or SAE on the CRF. If a diagnosis is 
subsequently established, it should be reported as follow-up information. 
• Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause. For example, if severe diarrhea is 
known to have resulted in dehydration, it is sufficient to record only diarrhea as an AE or 
SAE on the CRF.  
However, clinically significant AEs occurring secondary to an initiating event that are 
separated in time should be recorded as independent events on the CRF. For example, if a 
severe gastrointestinal hemorrhage leads to renal failure, both events should be recorded 
separately on the CRF. 
• Abnormal Laboratory Values 
Only clinically significant laboratory abnormalities that require active management will be 
recorded as AEs or SAEs on the CRF (e.g., abnormalities that require study drug dose 
modification, discontinuation of study treatment, more frequent follow-up assessments, 
further diagnostic investigation, etc.). 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 x the upper limit of normal associated with 
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cholecystitis), only the diagnosis (e.g., cholecystitis) needs to be recorded on the Adverse 
Event CRF. 
If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded as an AE or SAE on the CRF. If the laboratory 
abnormality can be characterized by a precise clinical term, the clinical term should be 
recorded as the AE or SAE. For example, an elevated serum potassium level of 7 mEq/L 
should be recorded as “hyperkalemia”. 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded as AEs or SAEs on the CRF, unless their severity, 
seriousness, or etiology changes. 
• Preexisting Medical Conditions (Baseline Conditions) 
A preexisting medical condition should be recorded as an AE or SAE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on an Adverse Event CRF, it is important to convey the concept that the preexisting 
condition has changed by including applicable descriptors (e.g., “more frequent 
headaches”). 
17.2  Grading and Reporting Adverse Events 
• Grading and Relationship to Drug 
The descriptions and grading scales found in the CTEP Version 5 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting. 
CTEP Version 5 of the CTCAE is identified and located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm  
AEs not covered by specific terminology listed should be reported with common medical 
terminology, and documented according to the grading scales provided in the CTCAE 
Version 5. 
The relationship of event to study drug will be documented by the Investigator as follows: 
Unrelated: The event is clearly related to other factors such as the participant’s clinical 
state, other therapeutic interventions or concomitant drugs administered to the participant. 
Unlikely: The event is doubtfully related to investigational agent(s). The event was most 
likely related to other factors such as the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs. 
Possible: The event follows a reasonable temporal sequence from the time of drug 
administration, but could have been produced by other factors such as the participant’s 
clinical state, other therapeutic interventions or concomitant drugs. 
Probable: The event follows a reasonable temporal sequence from the time of drug 
administration, and follows a known response pattern to the study drug. The event cannot 
be reasonably explained by other factors such as the participant’s clinical state, therapeutic 
interventions or concomitant drugs. 
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Definite: The event follows a reasonable temporal sequence from the time of drug 
administration, follows a known response pattern to the study drug, cannot be reasonably 
explained by other factors such as the participant’s condition, therapeutic interventions or 
concomitant drugs; AND occurs immediately following study drug administration, 
improves upon stopping the drug, or reappears on re-exposure. 
• Reporting Adverse Events: 
Routine AEs occurring between the start date of intervention until 30 days after the last 
intervention, or until the event has resolved, the study participant is lost to follow-up, the 
start of a new treatment, or until the study investigator assesses the event(s) as stable or 
irreversible, will be reported. New information will be reported after it is received. 
Guidelines for Routine Adverse Event Reporting for Phase 1 Studies (Regardless of 
Expectedness) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Unrelated 
X 
X 
X 
X 
Unlikely 
X 
X 
X 
X 
Possible 
X 
X 
X 
X 
Probable 
X 
X 
X 
X 
Definite 
X 
X 
X 
X 
17.3 Serious Adverse Events 
A serious adverse event (SAE) is any adverse event (experience) that in the opinion of either the 
investigator or sponsor results in ANY of the following: 
• Death. 
• A life-threatening adverse event (experience). Any AE that places a participant or 
participants, in the view of the Investigator or sponsor, at immediate risk of death from the 
reaction as it occurred. It does NOT include an AE that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours). 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly or birth defect. 
• Important Medical Event (IME) that, based upon medical judgment, may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
Reporting Serious Adverse Events 
All new SAEs occurring from the date the participant signs the study consent until 30 days after 
the last intervention or a new treatment is started, whichever comes first, will be reported. The 
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Roswell Park SAE Source Form is to be completed with all available information, including a brief 
narrative describing the SAE and any other relevant information.  
SAEs occurring after the 30 day follow-up period that the investigator determines to be possibly, 
probably or definitely related to the study intervention should be reported. 
SAEs identified as an Unanticipated Problem by the Investigator must be reported. Please refer to 
Section 17.5 for details on reporting Unanticipated Problems. 
17.4 Follow-Up for Serious Adverse Events 
All related SAEs should be followed to their resolution, until the study participant is lost to 
follow-up, the start of a new treatment, or until the study investigator assesses the event(s) as stable 
or irreversible. New information will be reported when it is received. 
17.5 Unanticipated Problems 
An Unanticipated Problem (UP) is any incident, experience, or outcome that meets all of the 
following criteria: 
• Unexpected (in terms of nature, severity, or frequency) given: 
o The research procedures that are described in the study-related documents, 
including study deviations, as well as issues related to compromise of participant 
privacy or confidentiality of data. 
o The characteristics of the participant population being studied. 
• Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research). 
• Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized and if in relation to an AE is also deemed Serious per Section 17.3. 
Reporting Unanticipated Problems: 
The Reportable New Information (RNI) Form will be submitted to the CRS Quality Assurance 
(QA) Office within 1 business day of becoming aware of the Unanticipated Problem. After review, 
CRS QA Office will submit the RNI to the IRB. 
When becoming aware of new information about an Unanticipated Problem, submit the updated 
information to CRS QA Office with an updated Reportable New Information Form. The site 
Investigator or designated research personnel will report all unanticipated problems to the IRB in 
accordance with their local institutional guidelines. 
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17.6 FDA Reporting 
When Roswell Park is the IND holder the following describes the FDA reporting requirements by 
timeline for AEs and new safety findings that meet the criteria outlined below: 
Within 7 Calendar Days 
Any adverse event that meets ALL the following criteria: 
• Related or possibly related to the use of the study drug; 
• Unexpected; and 
• Fatal or life-threatening. 
Within 15 Calendar Days 
Any adverse event that meets ALL the following criteria: 
• Related or possibly related to the use of the study drug; 
• Unexpected; and 
• Serious but not fatal or life-threatening; 
Or, meets ANY of the following criteria: 
• A previous adverse event that is not initially deemed reportable but is later found to fit the 
criteria for reporting (report within 15 days from when event was deemed reportable). 
• Any findings from other studies, including epidemiological studies, pooled analysis of 
multiple studies, or other clinical studies conducted with the study drug that suggest a 
significant risk in humans exposed to the drug. 
• Any findings from animal or in vitro testing that suggest a significant risk for human 
participants including reports of mutagenicity, teratogenicity, or carcinogenicity or reports 
of significant organ toxicity at or near the expected human exposure. 
• Any clinically important increase in the rate of occurrence of a serious, related or possibly 
related adverse event over that listed in the protocol or investigator brochure. 
Sponsors are also required to identify in IND safety reports, all previous reports concerning similar 
adverse events and to analyze the significance of the current event in the light of the previous 
reports. 
Reporting Process 
The principal investigator or designee will complete and submit a FDA Form 3500A MedWatch 
for any event that meets the above criteria. Forms will be submitted to the CRS QA Office via 
email to CRSQA@RoswellPark.org. 
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18 DATA MANAGEMENT AND CONFIDENTIALITY 
18.1 Data Collection 
Full build studies are managed by Roswell Park CRS Data Management for analysis by Roswell 
Park Biostatisticians. All electronic case report form (eCRF) data are captured for these studies. 
Data management activities are performed using a CTMS system that enables the collection, 
cleaning and viewing of clinical trial data. CRS data management designs the study-specific 
database and facilitates development by the Information Technology team. Once the database 
design is approved by the Investigator, Statistician, and Clinical Research Coordinator, the 
database is put into production and data entry can begin. Data can be entered and changed only by 
those with the rights to do so into the eCRFs. 
18.2 Maintenance of Study Documents 
Essential documents will be retained per Roswell Park’s policy for 6 years from the study 
termination date. These documents could be retained for a longer period, however, if required by 
the applicable local regulatory requirements or by an agreement with Roswell Park. 
18.3 Revisions to the Protocol 
Roswell Park may make such changes to the protocol as it deems necessary for safety reasons or 
as may be required by the U.S. FDA or other regulatory agencies. Revisions will be submitted to 
the IRB/ERC for written approval before implementation. 
18.4 Termination of the Study 
It is agreed that, for reasonable cause, either the Roswell Park Investigators or the Sponsor, may 
terminate this study, provided a written notice is submitted within the time period provided for in 
the Clinical Trial Agreement. In addition, Roswell Park may terminate the study at any time upon 
immediate notice if it believes termination is necessary for the safety of participants enrolled in 
the study. Any deaths on the clinical trial deemed related to the study drugs will necessitate trial 
suspension, review and possible termination. 
18.5 Confidentiality 
Refer to section 25.0 “Provisions to Protect the Privacy Interests of Subjects”. 
19 STATISTICAL PLAN 
This is a Phase I safety and tolerability trial evaluating the combination of chemokine modulation 
with neoadjuvant chemotherapy in triple negative breast cancer. 
Statistical analysis will be performed by the Roswell Park Biostatistics & Bioinformatics 
Department. 
19.1 Demographics and Baseline Characteristics 
Descriptive statistics (as appropriate: n, percent, mean, median, min and max) will be used to 
summarize demographic and baseline characteristics. 
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19.2 Analysis Cohorts 
Analysis Cohorts: 
Safety Cohort: All subjects that receive any study treatment will be included in the safety summary. 
Dose Escalation Cohort: Any subjects who receive study treatment and complete the DLT period 
(or fail to complete the DLT period due to toxicity) will be included in the dose escalation cohort. 
Patient Replacement: Patients who are unevaluable for DLT (i.e. disease progression prior to 
completion of CKM or patient refusal will be replaced for the primary safety analysis (i.e. 
identification of the MTD) and efficacy analyses. Patients who fail to complete at least 6 out of 
the 9 planned CKM doses (due to non-DLT related reasons) are not considered evaluable for the 
primary safety analysis and will be replaced. Data from patients who received only a part of the 
experimental regimen (<6 doses of CKM) may be evaluated in the exploratory manner for 
secondary/exploratory outcomes.  
19.3 Sample Size Determination 
The sample size determination is based on the primary analysis; which evaluates the safety of the 
treatment combination using an accelerated titration design. The exact sample size depends on the 
unknown dose-toxicity relationship. However, based on the number of dose-levels and decision 
rules, no more than 24 subjects will be required. Based on prior experience and the specified dose 
levels, we expect no more than 6-9 evaluable subjects to be enrolled. 
19.4 Primary Analysis: Dose Escalation 
The primary objective of this study is to evaluate safety and identify the appropriate dose level of 
Interferon alpha-2b in combination with celecoxib, rintatolimod, and paclitaxel. 
An accelerated titration design will be utilized to identify the appropriate dose-level for a future 
study. A single patient will be enrolled at dose level 1 (no Interferon alpha-2b). If a DLT is 
observed, then the standard 3+3 design will be triggered. If no DLT is observed, then a single 
patient will be enrolled at dose level 2. 
If a DLT or 2 cumulative moderate toxicities are observed at dose level 2, then the standard 3+3 
design will be triggered. Otherwise, a single patient will be enrolled at dose level 3. 
If a DLT or 2 cumulative moderate toxicities are observed at dose level 3, then the standard 3+3 
design will be triggered. Otherwise, 3 patients will be enrolled at dose level 4.  
If a DLT or 2 cumulative moderate toxicities are observed at dose level 4, then the standard 3+3 
design will be triggered. Otherwise, the study will be deemed complete. 
3+3 Dose Escalation 
As of Amendment 10, the 3+3 dose escalation design has been triggered at dose level 3 due to a 
treatment delay and dose reduction. An additional n=2 patients will be enrolled at dose level 3. If 
1 DLT is observed, then an additional n=3 patients will be enrolled at dose level 3. If DLTs are 
observed in 0 of 2 or 1 of 5, then n=3 patients will be enrolled at dose level 4 (and standard 3+3 
rules will apply). If 2 or more DLTs are observed, then n=2 patients will be enrolled at dose level 
2 (and standard 3+3 rules will apply). 
 
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19.5 
Secondary and Exploratory Analysis 
The secondary objectives are to evaluate: 1) the immunomodulatory effect of CKM and paclitaxel 
in the tumor microenvironment; 2) safety of the combination, 3) complete pathological response 
(pCR) and complete breast MRI response after 12 weeks and, 4) overall and recurrence-free 
survival. The safety and response outcomes are treated as dichotomous variables. 
Immunomodulatory effect of CKM 
The tumor infiltrating CD8+ CTLs, which are treated as continuous variables and will be 
summarized by time-point using the mean and standard deviation; and graphically using box- or 
dot-plots. The mean change in tumor infiltrating CD8+ CTLs (baseline to post-treatment) will be 
evaluated using a one-sided, permutation paired t-test about the following hypotheses: 
 
𝐻𝐻0: 𝜇𝜇𝑑𝑑= 0 versus 𝐻𝐻𝐴𝐴: 𝜇𝜇𝑑𝑑> 0, 
where 𝜇𝜇𝑑𝑑 is the true mean change in tumor infiltrating CD8+ CTLs. A 90% confidence interval 
about the mean change will be obtained using standard methods. Transformations or non-
parametric methods (i.e. sig test) will be used as appropriate. 
Safety 
All adverse events (AEs), serious AEs (SAEs), and toxicities will be summarized by attribution ( 
overall and related/ unrelated to treatment) and grade using frequencies and relative frequencies.   
Response Assessments 
The response data will be summarized using frequencies and relative frequencies. A 90% 
confidence interval about the true pCR rate will be obtained using Jeffrey’s prior method. The pCR 
rate will be compared to the historic pCR for standard neoadjuvant chemotherapy alone 
(approximately 0.26) using a one-sided binomial exact test 
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Survival Outcomes 
Overall and recurrence-free survival will be summarized using standard Kaplan-Meier methods; 
where estimates of the median and 3years rates will be estimated with 90% confidence intervals. 
19.6 Interim Analysis and Criteria for Early Termination 
There are no formal interim analyses or rules for early termination based on efficacy. The study is 
monitored for safety, with rules allowing for study suspension. 
The study will be monitored by the Roswell Park Data Safety and Monitoring Committee, who 
may make recommendations about study continuation and termination. 
20 PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF 
SUBJECTS 
All Roswell Park Phase I studies are reviewed at the scheduled Early Phase Clinical Trial 
Committee meetings and the minutes are forwarded to the IRB for review. 
In addition, the Roswell Park Data Safety Monitoring Committee will assess the progress of the 
study, the safety data, and critical efficacy endpoints (Phase I studies will be reviewed quarterly; 
Phase II, III and pilot investigator-initiated studies will be reviewed semi-annually). The DSMC 
will review the study and will make recommendations that include but not limited to; (a) 
continuation of the study, (b) modifications to the design (c) or termination of the study. 
21 VULNERABLE POPULATIONS 
Not applicable. 
22 COMMUNITY-BASED PARTICIPATORY RESEARCH 
Not applicable. 
23 SHARING OF RESULTS WITH SUBJECTS 
Individual response data is shared with the participant as a part of their clinical care. 
24 SETTING 
Potential subjects with breast cancer will be identified and recruited during scheduled visits to 
Roswell Park. Potential subjects, who are referred by their Roswell Park or community physicians, 
will be scheduled with an investigator in the clinic for evaluation. All participant related research 
procedures will be conducted at Roswell Park. 
25 PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF SUBJECTS 
Any data, specimens, forms, reports, video recordings, and other records that leave the site will be 
identified only by a participant identification number (Participant ID, PID) to maintain 
confidentiality. All records will be kept in a limited access environment. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without 
written authorization of the participant. 
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26 RESOURCES AVAILABLE 
Not applicable. 
27 PRIOR APPROVALS 
Not applicable. 
28 COMPENSATION FOR RESEARCH-RELATED INJURY 
If the subject believes they have been injured as a direct result of their participation in this research 
study, they will be advised to notify the Roswell Park Patient Advocate at (716) 845-1365 or the 
Study Doctor at (716) 845-1486. 
Medical diagnosis and treatment for the injury will be offered, and a determination will be made 
regarding appropriate billing for the diagnosis and treatment of the injury. A financial counselor 
(716-845-3161) will be able to provide an explanation of coverage and to answer questions the 
subject may have regarding study related billing. 
The subject is not prevented from seeking to collect compensation for injury related to malpractice, 
fault, or blame on the part of those involved in the research. 
29 ECONOMIC BURDEN TO SUBJECTS 
The participants will not be subject to any economic burden. 
30 CONSENT PROCESS 
This study will not be initiated until the protocol and informed consent document(s) have been 
reviewed and approved by a properly constituted Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC). Each participant (or legal guardian) shall read, understand, and sign an 
instrument of informed consent prior to performance of any study-specific procedure. It is the 
responsibility of the investigator to ensure that the participant is made aware of the investigational 
nature of the treatment and that informed consent is given. 
The Investigator is responsible for the retention of the participant log and participant records; 
although personal information may be reviewed by authorized persons, that information will be 
treated as strictly confidential and will not be made publicly available. The investigator is also 
responsible for obtaining participant authorization to access medical records and other applicable 
study specific information according to Health Insurance Portability and Accountability Act 
regulations (where applicable). 
This study will be conducted in compliance with all applicable laws and regulations of the state 
and/or country and institution where the participant is treated. The clinical trial should be 
conducted in accordance with the ethical principles embodied in the Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research, consistent with good 
clinical practice and the applicable regulatory requirements and according to the guidelines in this 
protocol, including attached appendices. 
Informed consent will be obtained according to SOP: Informed Consent Process for Research 
(HRP-090). 
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31 PROCESS TO DOCUMENT CONSENT IN WRITING 
The Investigator (or IRB specified designee) is responsible for obtaining written consent from each 
participant or the participant's legally authorized representative in accordance with GCP guidelines 
using the approved informed consent form, before any study specific procedures (including 
screening procedures) are performed. The informed consent form acknowledges all information 
that must be given to the participant according to applicable GCP guidelines, including the purpose 
and nature of the study, the expected efficacy and possible side effects of the treatment(s), and 
specifying that refusal to participate will not influence further options for therapy. Any additional 
information that is applicable to the study must also be included. Additional national or 
institutionally mandated requirements for informed consent must also be adhered to. The 
participant should also be made aware that by signing the consent form, processing of sensitive 
clinical trial data and transfer to other countries for further processing is allowed. 
The Investigator shall provide a copy of the signed consent form to the participant and the signed 
original shall be maintained in the Investigator File. A copy of the signed consent form must be 
filed in the participant file. At any stage, the participant may withdraw from the study and such a 
decision will not affect any further treatment options. 
SOP: Written Documentation of Consent (HRP-091) will be followed. 
32 DRUGS OR DEVICES 
Roswell Park will hold the IND for this study. 
32.1 Doxorubicin, Cyclophosphamide and Paclitaxel 
Doxorubicin, cyclophosphamide and paclitaxel are commercially available and will be dispensed 
per standard of care. These drugs will not be provided by the study and will be paid for by the 
patient’s insurance carrier as part of standard of care treatment. 
32.2 Celecoxib 
A sulfa non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, 
rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms, and to reduce 
numbers of colon and rectum polyps in patients with familial adenomatous polyposis. 
32.2.1 Other Names 
Celebrex, Celebra or Onsenal (commercially available) 
32.2.2 Formulation and Packaging 
Celecoxib as capsules in the following dosages: 100 mg and 200 mg. 
32.2.3 Drug Shipment 
Celecoxib will be provided by Roswell Park. 
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32.2.4 Drug Administration 
Celecoxib 200 mg will be administered orally twice a day approximately 12 hours apart on the 
days the patient receives the CKM regimen. The morning dose will be given to the participant at 
the same time as the other pre-medications for the CKM regimen. The evening dose of celecoxib 
will be self-administered by the participant at home and documented on the patient diary. Refer to 
Appendix H. 
32.2.5 Drug Storage and accountability 
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited access facility in accordance with the applicable 
regulatory requirements.   
Store celecoxib at room temperature (77°F/ 25°C) away from light and moisture. Brief storage 
between 59-86 °F (15-30 °C) is permitted. 
Drug storage temperature will be maintained and recorded, as applicable. 
32.3 Interferon Alpha-2b 
A drug approved around the world for the treatment of chronic hepatitis C, chronic hepatitis B, 
hairy cell leukemia, chronic myelogenous leukemia, multiple myeloma, follicular lymphoma, 
carcinoid tumor, and malignant melanoma. Interferon alpha-2b has many drug classifications 
including anti-infective, anti-neoplastic, antiproliferative, antiviral and immunological agent. 
32.3.1 Formulation and packaging 
50 million units/ mL, lyophilized powder, which must be reconstituted prior to administration. 
• Vial size:10 million units/vial 
• Diluent: Compatible with normal saline, Ringer’s injection, lactated Ringer’s, and 5% 
sodium bicarbonate injection. Interferon alpha-2b should be reconstituted with 1 mL to 
reach a final concentration of 10:1. IV dose should be diluted in sodium chloride 
0.9%/100 mL and given over 20 minutes. The final concentration of INTRON A should 
not be less than 10 million International Units/100 mL 
• Source: Schering Plough Corp. 
32.3.2 Drug Shipment 
Interferon alpha-2b will be provided by Roswell Park. 
32.3.3 Preparing and Dispensing 
The lyophilized product is reconstituted as directed by the manufacturer. Investigational Drug 
Service Pharmacy (IDS) will prepare and dispense. 
32.3.4 Drug Administration 
Interferon alpha-2b will be administered intravenously over 20 minutes. 
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32.3.5 Drug Storage and Accountability 
The Investigator or designate will be responsible for ensuring that the investigational product is 
securely maintained in a locked, limited-access facility in accordance with the applicable 
regulatory requirements. 
Powder for injection should be stored at 2 to 8°C (36-46°F). After reconstitution, the solution 
should be used immediately but may be stored up to 24 hours at 2-8°C (36-46°F). 
Drug storage temperature will be maintained and recorded, as applicable. 
32.3.6 Concomitant Medications 
Interactions between interferon alpha-2b and other drugs have not been fully evaluated (see 
Appendix I). Caution should be exercised when administering interferon alpha-2b therapy in 
combination with other potentially myelosuppressive agents such as zidovudine. Concomitant use 
of interferon alpha-2b and theophylline decreases theophylline clearance, resulting in a 100% 
increase in serum theophylline levels. Concomitant interferon alpha-2b and REBETOL (Ribavirin) 
use is contraindicated. 
32.4 Rintatolimod (poly IC analog) 
A substituted double stranded polyribonucleic acid (polyI: polyC12U), rintatolimod preserves 
activity of polyIC with a much improved systemic toxicity profile. The product has been studied 
extensively for use as a vaccine adjuvant and for its direct antiviral activity, as well in several 
cancer studies as a monotherapy, but most extensively in chronic fatigue syndrome (CFS). 
32.4.1 Other Names 
polyIC12U, Ampligen®, poly I: polyC12U; Polyinosinic: polycytidylic-polyuridylic acid; 
polyriboinosinic/polyribocytidylic (uridylic) acid 
32.4.2 Formulation and Packaging 
Rintatolimod is supplied as a liquid solution in glass bottles containing 200 mg (100 mg in case of 
toxicity) per 80 mL. Rintatolimod is a colorless solution containing 2.5 mg/mL in physiological 
salts (0.15 M NaCl, 0.01 M phosphate, 0.001 M Mg++). The product does not contain 
preservatives or antioxidants. 
32.4.3 Drug Shipment 
Rintatolimod will be provided by Hemispherix and shipped to the participating site. 
The date of receipt and the amount of drug received will be documented. Drug shipment records 
will be retained by the investigational pharmacist or designee. 
32.4.4 Preparing and Dispensing 
A vial of rintatolimod is suitable for direct IV infusion. IDS will prepare and dispense. Each vial 
should be taken from the refrigerator and allowed to equilibrate to room temperature. 
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32.4.5 Drug Administration 
Rintatolimod 200 mg will be administered by intravenous infusion after Interferon alpha-2b. 
Additional details on the procedures for receiving, storing and using rintatolimod (Ampligen®) 
can be found in a separate document entitled “Procedures for Receiving, Storing, and Using 
Ampligen® (Poly I:Poly C12U) Liquid Solution”.  
The initial administration should begin at a slow rate of infusion (approximately 20 cc/ hour) and 
increase to 40 cc/hour after 30 minutes. Tubing should be flushed with 30 to 50 mL of normal 
saline solution upon completion. 
32.4.6 Drug Storage and accountability  
Rintatolimod should be stored at 2 to 8°C (36-46°F). 
Drug storage temperature will be maintained and recorded, as applicable. 
32.4.7 Handling and Disposal 
The Investigator or designee will be responsible for dispensing and accounting for all 
investigational drug provided by Hemispherix exercising accepted medical and pharmaceutical 
practices. Study drugs must be handled as cytotoxic agents and appropriate precautions taken per 
the institution’s environmentally safe handling procedures. All investigational drugs will be 
dispensed in accordance with the Investigator’s prescription or written order. 
All products dispensed will be recorded on a product accountability record. Records of product lot 
numbers and dates received will be entered on a product accountability form. This record will be 
reviewed by the Sponsor’s staff or representative during periodic monitoring visits. It is the 
Investigator’s responsibility to ensure that an accurate record of investigational drug issued and 
returned is maintained. 
Used vials (excess drug) will be destroyed according to standard practices after properly 
accounting for the dispensing. Partially used vials of study drug will not be re-used for other 
participants. 
Under no circumstances will the Investigator supply investigational drug to a third party or allow 
the investigational drug to be used in a manner other than as directed by this protocol. 
In regards to drug receipt, accountability and storage, SOP IDS-601 will be followed. 
 
 
 
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34 APPENDICES/SUPPLEMENTS 
 
 
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Appendix A ECOG Performance Status Scores 
 
Description 
Status 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
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. 
1 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
4 
Dead 
5 
 
 
 
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Appendix B INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM: 
INCLUSION CRITERIA 
Participant Name: __________________________________________________ 
Medical Record No.: _________________________________________________ 
Title: Phase I Clinical Trial Assessing the Combination of Chemokine Modulation with 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer 
INCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “Yes” or “N/A” for participant 
enrollment. 
Date 
 
 
 
1. Age ≥ 18 years of age. 
 
 
 
 
2. Have pathologically confirmed diagnosis of resectable triple 
negative breast cancer (ASCO/CAP guidelines will be used 
to define triple negative breast cancer). 
 
 
 
 
3. Must have measurable disease. Multi-centric disease is 
allowed. If patient has another lesion which is biopsied with 
ER/PR positive it will be Physician discretion for this 
eligibility criteria 
 
 
 
 
4. Prior therapy: No prior cytotoxic regimens are allowed for 
this malignancy. Participants may not have had prior 
chemotherapy, other targeted anticancer therapies, or prior 
radiation therapy to the ipsilateral breast for this 
malignancy. Prior bis-phosphonate therapy is allowed. 
 
 
 
 
5. Patient eligible for surgery as determined by patient’s 
surgeon. 
 
 
 
 
6. Patient must have a lesion amendable to biopsy, unless 
inaccessible and with PI approval. 
 
 
 
 
 
7. Have an ECOG performance status of ≤ 2. Refer to 
Appendix A. 
 
 
 
 
8. Participants of child-bearing potential must agree to use 
adequate contraceptive methods (e.g., hormonal or barrier 
method of birth control; abstinence) prior to study entry. 
Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this 
study, she should inform her treating physician 
immediately. 
 
 
 
 
9. Ability to swallow and retain oral medication. 
 
 
 
 
10. Ability to undergo MRI. 
 
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INCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “Yes” or “N/A” for participant 
enrollment. 
Date 
 
 
 
11. Must have adequate organ and marrow function present as 
defined below: 
-Platelets ≥ 100,000/µL 
-Hemoglobin ≥ 9 g/dL 
-Absolute Neutrophil Count (ANC) ≥ 1500/µL 
-Total bilirubin ≤ institutional upper limit of normal (ULN) 
-AST (SGOT) and ALT (SGPT) ≤ 1.5 X institutional ULN 
-Creatinine < ULN 
OR 
-Creatinine clearance ≥ 50 mL/min per Cockcroft-Gault 
Equation for     patients with creatinine levels greater than 
ULN-refer to Appendix D. 
 
 
 
 
12. Left Ventricular Ejection Fraction (LVEF) ≥ 55%. If LVEF 
is <55% and patient is otherwise study-eligible, the PI will 
discuss with cardiologist if patient is eligible to receive 
doxorubicin and participate in study. 
 
 
 
 
13. Participant or legal representative must understand the 
investigational nature of this study and sign an Independent 
Ethics Committee/Institutional Review Board approved 
written informed consent form prior to receiving any study 
related procedure. 
 
 
 
 
 
14. Participants on this study will be counselled on and are 
willing to use adequate contraceptive methods. 
 
Investigator Signature: ___________________________________ 
Date: ___________ 
Printed Name of Investigator: __________________________________________________ 
 
 
 
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Appendix C INVESTIGATOR STUDY ELIGIBILITY VERIFICATION FORM: 
EXCLUSION CRITERIA 
Participant Name:  ________________________________________________ 
Medical Record No.:  ______________________________________________ 
Title: Phase I Clinical Trial Assessing the Combination of Chemokine Modulation with 
Neoadjuvant Chemotherapy in Triple Negative Breast Cancer 
EXCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “No” or “N/A” for participant 
enrollment. 
Date 
 
 
 
1. Patients currently treated with systemic 
immunosuppressive agents, including steroids, are 
ineligible until 3 weeks after removal from 
immunosuppressive treatment.  
 
 
 
 
2. Patients with active autoimmune disease, requiring ongoing 
immunosuppressive therapy or history of transplantation. 
 
 
 
 
3. Diagnosis of invasive carcinoma within last 3 years. 
 
 
 
 
4. Inflammatory breast cancer will be excluded from the 
study. 
 
 
 
 
5. Participants who have metallic surgical implants that are 
not compatible with an MRI machine are not eligible. 
 
 
 
 
6. Pregnant or nursing female participants. 
 
 
 
 
7. Unwilling or unable to follow protocol requirements. 
 
 
 
 
8. Patients with known serious mood disorders (major 
depression is an exclusion). Other stable mood disorders on 
stable therapy for > 6 months may be allowed after 
consultation with PI) 
 
 
 
 
9. Cardiac risk factors including: 
-Patients experiencing cardiac event(s) (acute coronary 
syndrome, myocardial infarction, or ischemia) within 3 
months of signing consent. 
-Patients with a New York Heart Association classification 
of III or IV (Appendix E). 
 
 
 
 
10. History of upper gastrointestinal ulceration, upper 
gastrointestinal bleeding, or upper gastrointestinal 
perforation within the past 3 years. 
 
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with Neoadjuvant Chemotherapy in Triple Negative Breast Cancer 
 
 
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EXCLUSION CRITERIA 
Yes 
No 
N/A 
All answers must be “No” or “N/A” for participant 
enrollment. 
Date 
 
 
 
11. Prior allergic reaction or hypersensitivity to NSAIDs or 
any drugs administered on protocol. 
 
 
 
 
12. Any history of allergy to sulfonamides. 
 
 
 
 
13. Any history of autoimmune hepatitis  
 
 
 
 
14. Grade 1 or higher neuropathy 
 
 
 
 
15. Any condition which in the Investigator’s opinion deems 
the participant an unsuitable candidate to receive study 
drug. 
 
 
Participant meets all entry criteria: 
 
  Yes 
  No 
If “NO”, do not enroll participant in study. 
Investigator Signature: ___________________________________ 
Date: __________ 
Printed Name of Investigator: _________________________________________________
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Appendix D Cockcroft-Gault Equation 
Cockcroft-Gault Equation* 
Men: CrCl = [(140-YR) x IBW] / (PCr x 72) 
Women: CrCl = 0.85 x [(140-YR) x IBW] / (PCr x 72) 
Where: 
CrCl is creatine clearance (mL/min) 
IBW is ideal body weight (kg) 
PCr is plasma creatinine (mg/dL) 
YR is age (years) 
 
 
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Appendix E NYHA CLASSIFICATION 
 
 
 
 
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Appendix F RECIST 1.1 Criteria 
 
Objective Tumor Response 
All protocol-defined imaging studies must be performed at the investigative site or sponsor-
approved facility using protocol-defined parameters. The same method of assessment and the same 
technique should be used to characterize each identified and reported lesion at baseline and during 
follow-up. RECIST 1.1 will be used to assess objective tumor response. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, will be identified as target lesions and recorded and measured at baseline. 
Target lesions will be selected on the basis of their size. Lesions with the longest diameter (short 
axis for lymph nodes) and are ≥ 10 mm (CT and MRI), ≥ 15 mm lymph nodes, > 20 mm CXR and 
are for accurate repetitive measurements (either by imaging techniques or clinically) will be 
chosen. A sum of the longest diameter (short axis for lymph nodes) of all target lesions will be 
calculated and reported as the baseline sum diameters. This will be used as reference to further 
characterize the objective tumor response of the measurable dimension of the disease. 
Complete Response (CR): Disappearance of all target lesions. Any lymph nodes must have a 
reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the 
sum of diameters of target lesions, taking as reference the baseline sum diameters. Changes 
in tumor measurements must be confirmed by repeat studies performed no less than 
6 weeks after the criteria for response are first met. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as references the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. The appearance of one or more new 
lesions is also considered progression. 
Stable Disease (SD): Neither a sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameter while on study. 
Participants having a documented response with no confirmation of the response will be 
listed with stable disease. 
Non-Target Lesions 
All other small lesions (longest diameter < 10 mm or lymph nodes ≥ 10 mm to < 15 mm short 
axis) and non-measurable lesions (i.e., leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, blastic bone 
lesions, or abdominal masses / abdominal organomegaly identified by physical exam that is not 
measurable by imaging) should be identified as non-target lesions and indicated as present in the 
source documents at baseline. The general location will also be documented on the images drawing 
a regularly-shaped Region of Interest. Measurements of the non-target lesions will not be 
performed, but the presence or absence of each should be noted throughout follow-up and 
evaluation. 
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Complete Response: Disappearance of all non-target lesions and normalization of tumor 
marker level, if applicable. All lymph nodes must be non-pathological in size (< 10 mm 
short axis). 
Non-Complete Response/Non-Progressive Disease: Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the upper limits of normal. 
Progressive Disease: Appearance of 1 or more new lesions or the unequivocal progression of 
existing non-target lesions. Although a clear progression of non-target lesions is 
exceptional, in such circumstances, the opinion of the treating physician should prevail and 
the progression status should be confirmed at a later time. 
Cytology and Histology 
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors), where 
known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
Evaluation of Response 
Response assessments will be performed at the following time points: 
• Prior to start of doxorubicin and cyclophosphamide combination, after completion of last 
paclitaxel treatment 
• Prior to surgery, after completion of last dose of doxorubicin/cyclophosphamide 
To determine time point response, refer to tables below: 
 
Time Point Response Criteria: target (± non-target lesion) 
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Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Time Point Response Criteria: non-target disease only 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD1 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 Non-CR/non-PD is preferred over SD for non-target disease since SD is used as endpoint for 
assessment of efficacy in trials so to assign this category when no lesions can be measured is 
not advised. 
 
The best overall response is the best response recorded from the start of study treatment until the 
end of treatment or disease progression/recurrence, whichever occurs earlier, taking into account 
any requirement for confirmation. In general, the participant’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria and will be determined 
by combining the participant’s status of target lesions, non-target lesions, and new lesions. 
• Symptomatic Deterioration: Participants with global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that time, 
and not related to study treatment or other medical conditions should be reported as 
progressive disease due to “symptomatic deterioration.” Every effort should be made to 
document objective progression even after discontinuation of treatment due to 
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symptomatic deterioration. Symptomatic deterioration that may lead to discontinuation of 
treatment include, but is not limited to, symptoms such as: 
• Weight loss > 10% of body weight. 
• Worsening of 
disease-related symptoms (e.g., worsening dyspnea, increasing 
pain/increasing requirement for narcotic analgesics). 
• Decline in performance status of > 1 level on ECOG scale. 
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation. All baseline evaluations should 
be performed as closely as possible to the beginning of treatment and never more than  before the 
beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical Lesions: Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as 
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the 
slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the study, 
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confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, 
MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation 
is not advised. However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor Markers: Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a participant to be 
considered in complete clinical response. 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such 
as germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of 
FDG PET imaging can be identified according to the following algorithm: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The 
use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must 
be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
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Appendix G Adaption of Immune-Related Response Criteria (irRECIST) 
The following is taken from Bohnsack et al, 2014, 1070P-Adaptation of the Immune Related 
Response Criteria: irRECIST, Ann Oncol, 25 (suppl 4): iv369  doi:10.1093/annonc/mdu342.23 
(35). 
1. Baseline 
A. Measurable Lesion Definitions and Target Lesion Selection 
• Follow the definitions from RECIST 1.1 
• Measurable lesions must be accurately measured in at least one dimension with a 
minimum size of: 
o 10 mm in the longest diameter by CT or MRI scan (or no less than double the 
slice thickness) for non- nodal lesions and ≥ 15 mm in short axis for nodal 
lesions 
o 10 mm caliper measurement by clinical exam 
o 20 mm by chest X-ray 
B. Non-measurable Lesion Definitions 
• Follow the definitions from RECIST 1.1 
• Non-target lesions will include 
o Measurable lesions not selected as target lesions 
o All sites of non-measurable disease, such as neoplastic masses that are too small 
to measure because their longest uninterrupted diameter is < 10 mm (or < two 
times the axial slice thickness), i.e., the longest perpendicular diameter is ≥ 10 
and < 15 mm. 
o Other types of lesions that are confidently felt to represent neoplastic tissue, but 
are difficult to measure in a reproducible manner. These include bone 
metastases, leptomeningeal metastases, malignant ascites, pleural or pericardial 
effusions, ascites, inflammatory breast disease, lymphangitis cutis/pulmonis, 
cystic lesions, ill-defined abdominal masses, skin lesions, etc. 
C. Target and Non-target Lymph Node Lesion Definitions 
• Follow the definitions from RECIST 1.1 
D. Non-target Lesion Selection 
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• All lesions or sites of disease not recorded as target lesions should be recorded as non-
target lesions at baseline. There is no limit to the number of non-target lesions that can 
be recorded at baseline. 
E. Bone Lesions 
• Follow the definitions from RECIST 1.1 
• Regardless of the imaging modality blastic bone lesions will not be selected as target 
lesions. Lytic or mixed lytic-blastic lesions with a measurable soft tissue component 
≥ 10 mm can be selected as target lesions. 
F. Brain Lesions 
• Brain Lesions detected on brain scans can be considered as both target or non-target 
lesions. 
G. Cystic and Necrotic Lesions as Target Lesions 
• Lesions that are partially cystic or necrotic can be selected as target lesions.  
• The longest diameter of such a lesion will be added to the Total Measured Tumor 
Burden (TMTB) of all target lesions at baseline.  
• If other lesions with a non-liquid/non-necrotic component are present, those should be 
preferred. 
H. Lesions with Prior Local Treatment 
• During target lesion selection the radiologist will consider information on the 
anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, 
surgery, etc.). 
• Lesions undergoing prior intervention will not be selected as target lesions unless there 
has been a demonstration of progress in the lesion. 
I. No Disease at Baseline 
• If a patient has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available 
follow-up time-points unless new measurable lesions are identified and contribute to 
the TMTB. 
2. Follow-Up 
A. Recording of Target and New Measurable Lesion Measurements 
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• The longest diameters of non-nodal target and new non-nodal measurable lesions, and 
short axes of nodal target and new nodal measurable lesions will be recorded. Together 
they determine the Total Measured Tumor Burden (TMTB) at follow-up. 
B. Definition of New Measurable Lesions 
• In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions 
total, per time-point), new lesions must meet criteria as defined for baseline target 
lesion selection and meet the same minimum size requirements of 10 mm in long 
diameter and minimum 15 mm in short axis for new measurable lymph nodes. New 
measurable lesions shall be prioritized according to size, and the largest lesions shall 
be selected as new measured lesions. 
C. Non-target Lesion Assessment 
• The RECIST 1.1 definitions for the assessment of non-target lesions apply. 
• The response of non-target lesions primarily contributes to the overall response 
assessments of irCR and irNon-CR/Non-PD (irNN). 
• Non-target lesions do not affect irPR and irSD assessments.  
• Only a massive and unequivocal worsening of non-target lesions alone, even without 
progress in the TMTB is indicative of irPD. 
D. New Non-Measurable Lesions Definition and Assessment 
• All new lesions not selected as new measurable lesions are considered new non-
measurable lesions and are followed qualitatively.  
• Only a massive and unequivocal progression of new non-measurable lesions leads to 
an overall assessment of irPD for the time-point. 
• Persisting new non- measurable lesions prevent irCR. 
3. irRECIST Overall Tumor Assessments 
• irCR: complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. Confirmation of response is not mandatory. 
• irPR: decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions. 
• irSD: failure to meet criteria for irCR or irPR in the absence of irPD. 
• irNN: no target disease was identified at baseline and at follow-up the patient fails to meet 
criteria for irCR or irPD. 
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• irPD: minimum 20% increase and minimum 5 mm absolute increase in TMTB compared 
to nadir, or irPD for non-target or new non-measurable lesions. Confirmation of 
progression is recommended minimum 4 weeks after the first irPD assessment. 
• irNE: used in exceptional cases where insufficient data exists. 
• irND: in adjuvant setting when no disease is detected. 
 
For additional information, refer to the following article and online supplemental information: 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey 
J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella 
C, de Vries EG, group Rw. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e52. doi: 10.1016/S1470-2045(17)30074-8. 
PubMed PMID: 28271869. 
(36) 
 
 
 
 
 
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Appendix H Celecoxib Patient Diary 
 
Protocol # __________________ 
                 
     Patient Name:  ______________ 
Drug Name: Celecoxib  
      
  
 
 
 
 
 
     Med. Record #: ___ ___ ___ ___ ___ ___ 
 
Study Medication Calendar 
 
You are participating in a study that requires Celecoxib 200 mg to be given twice daily, 
approximately 12 hours (+/- 1 hour) apart on certain days. Your morning dose of Celecoxib will be 
given to you along with your pre-medications while you are in clinic. Please complete this 
calendar to document your evening doses of Celecoxib. Your nurse will let you know what time 
you receive your morning dose of Celecoxib so you can take your evening dose approximately 12 
hours after. 
 
 Pre-treatment Regimen #______: 
 
Date 
 
 
 
Time that morning 
dose was taken (to 
be completed by 
the nurse in clinic) 
 
 
 
Evening Dose 
 
 
 
Time 
 
 
 
Patient’s Initials 
 
 
 
 
 
Please remember to bring this calendar and your pill bottle (including any unused pills) 
with you to your next study appointment. 
_______________________________________________________________________________ 
 
Coordinator use only 
Date of return: __________________ 
# of pills 
 (dispensed: _______     --   returned: _______) 
        
 
 _____________________________________     x   100   =    % adherence: __________ 
     
 # of pills scheduled _______         
  
_______________________________________________________________________________ 
 
 
Patient signature: _________________________________________              Date: ____________ 
                                                                                                                   
Investigator signature: _____________________________________              Date: ____________ 
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Appendix I 
Description of Interferon Alpha-2b Potential Interactions 
Aldesleukin: Interferons (Alfa) may enhance the adverse/toxic effect of Aldesleukin. In 
particular, risks of myocardial and renal toxicity may be increased by this combination. 
Risk D: Consider therapy modification 
Methadone: Interferons (Alfa) may increase the serum concentration of Methadone. Risk C: 
Monitor therapy 
Ribavirin: Interferons (Alfa) may enhance the adverse/toxic effect of Ribavirin. Hemolytic 
anemia has been observed. Risk C: Monitor therapy 
Telbivudine: Interferon Alfa-2b may enhance the adverse/toxic effect of Telbivudine. 
Specifically, the risk for peripheral neuropathy may be increased. Risk X: Avoid 
combination 
Theophylline Derivatives: Interferons may decrease the metabolism of Theophylline 
Derivatives. Exceptions: Dyphylline. Risk C: Monitor therapy 
Zidovudine: Interferons may enhance the adverse/toxic effect of Zidovudine. Interferons may 
decrease the metabolism of Zidovudine. Risk C: Monitor therapy 
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Appendix J 
Dose Escalation Cohort Study Calendar 
 
Evaluation 
Baseline# 
Paclitaxel + 
CKM 
combination  
 
Weeks 1-3 
 
Paclitaxel 
monotherapy  
 
Day 1 of weeks 
4 through 12 
Doxorubicin + 
Cyclophosphamide 
 
Every 2 weeks on 
Day 1 ( 4 cycles) 
Pre-
Surgical 
Visit 
Surgery 
End of 
Treatment13 
D1 D2 D3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
X1 
X 
X 
X 
X 
X 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
 
 
X 
Medical and 
surgical history 
X 
 
 
 
 
 
 
 
 
Physical 
examination 
(including breast 
exam and 
measurement of 
breast lesion) 
X2 
X2a 
 
 
X2a 
X2 
X 
 
X 
Vital Signs3 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
 
X3 
Height/Weight4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
 
 
ECOG PS 
X 
X 
 
 
X 
X 
X 
 
X 
Hematology5 
X 
X 
 
 
X 
X 
X 
 
X 
Chemistry6 
X 
X 
 
 
X 
X 
X 
 
X 
TSH  
X 
 
 
 
 
 
 
 
 
Serum HCG 
X7 
 
 
 
 
 
 
 
 


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Evaluation 
Baseline# 
Paclitaxel + 
CKM 
combination  
 
Weeks 1-3 
 
Paclitaxel 
monotherapy  
 
Day 1 of weeks 
4 through 12 
Doxorubicin + 
Cyclophosphamide 
 
Every 2 weeks on 
Day 1 ( 4 cycles) 
Pre-
Surgical 
Visit 
Surgery 
End of 
Treatment13 
D1 D2 D3 
Correlative Studies 
 
X8 
 
 
 
 
 
 
 
MRI Breast 
X9 
 
 
 
X9 
X9a 
 
 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
 
 
 
 
X10 
 
Biopsy11 
X 
 
 
X 
 
 
 
 
 
Study Drug 
Administration 
 
 
 
 
 
 
 
 
 
Paclitaxel14  
 
X14 
 
 
X14 
 
 
 
 
CKM  
 
X12 
X 
X 
 
 
 
 
 
Doxorubicin 
 
 
 
 
 
X14 
 
 
 
Cyclophosphamide 
 
 
 
 
 
X14 
 
 
 
 
# Baseline assessments to be completed within 28 days of treatment start unless otherwise stated. 
1 
Medications ongoing, or discontinued, within 1 week prior to first dose of study drug. 
2 
Physical exam (including breast exam and measurement of breast lesions) is required prior to dosing on weeks +/- 3 days 
1,2,3, 4,5,6, 7, 10 and 12. During doxorubicin/cyclophosphamide treatment, physical exam will be performed every 2 
weeks on day of treatment, prior to dosing. 
2a: During the DLT period (Day 1 of Week 1 through Week 6, physical exam to include assessment of 
head/ears/eyes/nose/throat (HEENT), skin, chest/lungs, heart, neck/lymph nodes, abdomen, extremities. Ophthalmologic 
evaluation to be performed after week 6 if symptoms develop.  


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3 
Vital Signs include blood pressure, pulse, temperature and respiratory rate. On days that rintatolimod is given, vital signs 
will be obtained pre-treatment, 30 and 60 minutes post rintatolimod (± 5 minutes) 
4 
Weight is required prior to dosing on each dosing day. CKM dose will be recalculated if weight changes greater than 10%. 
Height is required at baseline only. 
5 
CBC with automated differential+/- 1 day 
6 
CMP+/- 1 day 
7 
Within 7 days of first dose of study drug in women of child-bearing potential. 
8 
60 cc of blood (five 10 cc green tops and one 10 cc red top) will be collected pre-chemotherapy dose on day 1 of week 1; 
30 minutes after completion of Rintatolimod on day 1 of week 1. 
9 
MRI breast will be done within 6 weeks +/- 3 days of baseline evaluations for study participants per standard of care. 
a. Only for the cohort at dose level 4: prior to start of doxorubicin/cyclophosphamide combination at least 1 day after last 
paclitaxel dose; and prior to surgery (standard of care) at least 2-3 weeks after last dose of 
doxorubicin/cyclophosphamide combination 
10 
Lumpectomy/ mastectomy done 3-6 weeks after the last dose of chemotherapy. Surgical outcome data collected. 
11 
All patients will be required to receive a paired biopsy on study. Biopsies will be performed at screening, and between 
Week 3 Day 3, and prior to infusion of Paclitaxel on Week 4 Day 1. 
12 
Day 1, 2, or 3 of each CKM dose may be delayed by 1 day for any reason (i.e. patient tolerance, etc.) In this instance, all 
CKM doses and corresponding assessments will be moved to days 2-4 instead of days 1-3. In the event that an assessment 
or labs was already performed on day 1 of that week, it does not need to be repeated on day 2 unless specifically indicated 
by the investigator. For example, if physical exam or labs was completed on day 1 and CKM start was delayed to day 2, the 
physical exam or labs does not need to be repeated.  
13 
End of treatment visit to occur 2 week (± 3 days) after surgery. After this visit, the patient will be followed as per standard 
of care if no drug related toxicity is observed. Survival status will be assessed by telephone contact or chart review every 6 
months from surgery for a max of 3 years, and then taken off study. Additionally (if applicable), the patient can be 
contacted by telephone until resolution of any drug-related toxicity. 
14 
Treatment can be administered +/- 3 days on the 1st day of every cycle