SUPPLEMENTARY MATERIAL
Supplementary Figure 1. Pain Evaluation as assessed by Present Pain Intensity Score. Absolute changes between cycle 2 and baseline.
Supplementary Table 1. Molecular Profiling Results (Sequenom and MiSeq Analyses) on Formalin-Fixed Paraffin Embedded Tumor Samples.
Con= concentration; Freq= Frequency. In blue: samples analyzed with Sequenom Panel. In black: samples analyzed with MiSeq.
Supplementary Table 2. Molecular Profiling Results performed on Formalin-Fixed Paraffin Embedded Tumor Samples of prostate cancer patients.
MAF: Minor Allele Frequency; LOVD: Leiden Open Variation Database
Supplementary Appendix 1. NCI8476/PJC-002 Protocol.
NCI Protocol #: 8476
Local Protocol #: PJC-002
TITLE: A Phase 2 Randomized Study of Cediranib (AZD2171) Alone Compared with the Combination of Cediranib (AZD2171) plus BMS-354825 (dasatinib, Sprycel) in Docetaxel Resistant, Castration Resistant Prostate Cancer
Coordinating Center: Princess Margaret Hospital Phase I Consortium
*Principal Investigator: Dr. Sebastien Hotte
Juravinski Cancer Centre
699 Concession Street
Hamilton, Ontario
L8V 5C2
Canada
Tel: 905-387-9495
Fax: 905-575-6326
Email:
Co-Investigators: Dr. Srikala Sridhar
Princess Margaret Hospital
610 University Avenue, Suite 5-222
Toronto, Ontario M5G 2M9
Canada
Tel: 416-946-4501 ext 2520
Fax: 416-946-6546
Email:
Dr. Lillian Siu
Princess Margaret Hospital
610 University Avenue, Suite 5-718
Toronto, Ontario
M5G 2M9
Canada
Tel: 416-946-2911
Fax: 416-946-4467
Email:
Co-Investigators: Dr. Michael Carducci
Johns Hopkins University
Hopkins Kimmel Cancer Center
1650 Orleans Street
1M59CRB
Baltimore, MD
21231-1000 USA
Tel: 410-614-3977
Fax: 410-614-8160
Email:
Dr. Hans Hammer
Johns Hopkins University
Hopkins Kimmel Cancer Center
1650 Orleans Street
1M59CRB
Baltimore, MD
21231-1000 USA
Tel: 410-502-4658
Fax: 410-614-8397
Email:
Dr. Robert DiPaola
UMDNJ-The Cancer Institute of New Jersey
195 Little Albany Street, Suite 2002B
New Brunswick, NJ
08903 USA
Tel: 732-235-8064
Fax: 732-235-8094
Email:
Dr. Kim Chi
BC Cancer Agency
600 West 10th Avenue
Vancouver, British Columbia
V5Z 4E6
Canada
Tel: 604-877-6000
Fax: 604-877-0585
Email:
Co-Investigators: Dr. David C. Smith
University of Michigan
1500 E. Medical Center Dr.
7302 Cancer Center, SPC 5946
Ann Arbor, MI 48109-5946
Tel: 734-936-6884
Fax: 734-615-2719
Email:
Statistician: Study Coordinator:
Lisa Wang Tracy Wong
Princess Margaret Hospital Princess Margaret Hospital
610 University Avenue 620 University Avenue, Room 6-606
Toronto, Ontario M5G 2M9 Toronto, Ontario, M5G 2M9
Canada Canada
Tel: 416-946-4501 ext 4883 Tel: 416-946-4501 ext 5509
Fax: 416-946-2048 Fax: 416-946-4607
E-mail: E-mail:
Program Manager:
Robin Cheiken
Princess Margaret Hospital
610 University Avenue, Room 4-743
Toronto, Ontario M5G 2M9
Canada
Tel: 416-946-4616
Fax: 416-946-4607
Email:
NCI Supplied Agents: Cediranib (AZD2171, Recentin™, NSC#732208, IND#72740) and Dasatinib (BMS-354825) (NSC 732517; IND 73969)
Protocol version date: July 05, 2010
Amendment # 1: October 25, 2010
Amendment #2: December 23, 2010
Amendment #3: February 7, 2011
Amendment #4: March 21, 2011
Amendment #5: July 15, 2011
Amendment #6: December 15, 2011
Amendment #7: April 25, 2012
SCHEMA
This is a randomized, phase II trial of cediranib (AZD2171) with or without dasatinib (BMS-354825) in patients with docetaxel-resistant, castration resistant prostate cancer (CRPC)
Key Eligibility:
· Patients with castration resistant prostate cancer that progressed on or after first-line chemotherapy treatment with docetaxel
· Patients must have radiological documentation of either measurable or non-measurable disease
· ECOG 0-2, with adequate organ function
Treatment:
Arm A
cediranib (AZD2171) 20 mg PO daily and continuously starting day 1 on a 28-day cycle
Arm B
cediranib (AZD2171) 20 mg PO daily and continuously starting day 1 on a 28-day cycle
dasatinib (BMS-354825) 100 mg PO daily and continuously starting day 1 on a 28-day cycle
Design:
· Randomized phase II trial with a comparative design, α = 0.15 (one-sided) and power = 0.8
· Total sample size = 50 evaluable patients
· Primary endpoint: progression free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2) which is a composite endpoint of PSA, bone scan, CT scan assessments(1)
· Secondary endpoints:
o Safety and tolerability of the combination and cediranib alone
o For patients with measurable disease, objective response rates will be calculated according to RECIST criteria
o Symptom assessment by FACT-P questionnaire and Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire
o Laboratory-based biomarkers to correlate to clinical outcome: bone resorption markers (e.g. c-telopeptide and bone alkaline phosphatase)
SCHEMA
TABLE OF CONTENTS
Page
SCHEMA iv
1. OBJECTIVES 1
1.1 Primary Objectives 1
1.2 Secondary Objectives 1
2. BACKGROUND 1
2.1 Castration Resistant Prostate Cancer 1
2.2 Dasatanib (BMS-354825) 2
2.3 Cediranib (AZD2171) 10
2.4 Rationale for Combining Cediranib and Dasatinib in CRPC 13
2.5 Correlative Studies Background 15
3. PATIENT SELECTION 16
3.1 Eligibility Criteria 16
3.2 Exclusion Criteria 18
3.3 Inclusion of Minorities 21
4. REGISTRATION PROCEDURES 22
4.1 General Guidelines 22
4.2 Registration Process 23
4.3 Randomization and Stratification...... 23
5. TREATMENT PLAN 24
5.1 Cediranib (AZD2171) and Dasatinib (BMS-34825) Administration 24
5.1.1 Arm A: Cediranib (AZD2171) Alone 24
5.1.2 Arm B: Cediranib (AZD2171) and Dasatinib (BMS-354825) 25
5.2 General Concomitant Medication and Supportive Care Guidelines 26
5.2.1 Risk Mitigation for Pulmonary Arterial Hypertension…………….………28
5.3 Duration of Therapy 28
5.4 Duration of Follow Up 29
6. DOSING DELAYS/DOSE MODIFICATIONS 29
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 37
7.1 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 37
7.2 Adverse Event Characteristics 43
7.3 Expedited Adverse Event Reporting 43
7.4 Routine Adverse Event Reporting 45
7.5 Secondary AML/MDS reporting 45
8. PHARMACEUTICAL INFORMATION 46
8.1 Cediranib (AZD2171) 46
8.2 Dasatinib (BMS-354825) 47
8.3 Agent Ordering, Accountability, and Returns 48
9. CORRELATIVE/SPECIAL STUDIES 50
9.1 Archival Specimens 50
9.2 Bone Resorption Markers 50
9.3 Quality of Life Questionnaires and Pain Assessment 51
10. STUDY CALENDAR 52
11. MEASUREMENT OF EFFECT 54
12. DATA REPORTING / REGULATORY REQUIREMENTS 61
12.1 Data Reporting…………………………………………………………………….. 61
12.2 CTEP Multicenter Guidelines……………………………………………………. 62
12.3 Cooperative Research and Development Agreement (CRADA)/
Clinical Trials Agreement (CTA)…………………………………………………. 62
13. STATISTICAL CONSIDERATIONS 65
REFERENCES 67
SAMPLE CONSENT 71
APPENDICES
APPENDIX A
Drugs Known to be Metabolized by Selected CYP450 Isoenzymes.………………………..86
APPENDIX B
Performance Status Criteria 91
APPENDIX C
NYHA Cardiovascular Disability Classification 92
APPENDIX D
Patient Pill Diary 93
APPENDIX E
Patient’s Blood Pressure Diary 97
APPENDIX F
FACT-P Questionnaire (version 4) 99
APPENDIX G
Present Pain Intensity (PPI) Questionnaire (version 4) 102
APPENDIX H
Data Management Guidelines 103
APPENDIX I
CTEP Multicenter Guidelines 105
77
1. OBJECTIVES
1.1. Primary Objectives
1.1.1 To determine and compare the efficacy of cediranib versus cediranib plus dasatinib in the treatment of docetaxel-resistant, castration resistant prostate cancer (CRPC) using progression free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2) which is a composite endpoint of PSA, bone scan, and CT scan assessments
1.2. Secondary Objectives
1.2.1 To confirm the safety and tolerability of cediranib with or without dasatinib
1.2.2 To calculate objective response rates of cediranib with or without dasatinib according to RECIST criteria for patients with measurable disease at baseline
1.2.3 To perform symptom assessment using the FACT-P questionnaire and the present pain intensity (PPI) scale from the McGill-Melzack questionnaire
1.2.4 To explore bone resorption markers (e.g. c-telopeptide and bone alkaline phosphatase), and to correlate these biomarkers with clinical outcome
2. BACKGROUND
2.1. Castration Resistant Prostate Cancer
Prostate cancer is the most common cancer diagnosed and the second most common cause of cancer death in men in North America.(2) Because patients with locally advanced and metastatic disease have a poor prognosis, identification of novel targets and therapeutic agents that act against them is a main goal. Prostate cancer is a hormone sensitive tumor. However, after receiving hormonal treatment, the majority of prostate cancer patients become resistant to this approach over time. Indeed, the development of androgen independent disease or castration resistant prostate cancer (CRPC) is inevitable. Once patients develop clinical CRPC, therapeutic options are limited and prognosis is poor.(3) Chemotherapy is the standard of care for CRPC. Docetaxel has recently been considered the new standard cytotoxic agent based on the results of two randomized trials that reported a statistically significant increase in median survival.(4, 5) For patients that progressed despite docetaxel based chemotherapy, no standard treatment has yet demonstrated any significant clinical benefit. In this context, the development of therapeutic strategies for docetaxel-resistant and castration resistant patients would fulfill a relevant unmet need in prostate cancer research.
Different biologic mechanisms have been associated with the development of CRPC. Activation of growth factor receptors including the vascular endothelial growth factor receptor (VEGFR), and its downstream pathway mediators such as the oncogenic Src pathway have been implicated in this neoplastic process(6) and represent potential targets.
2.2. Dasatinib (BMS-354825)
Dasatinib (BMS-354825), an aminothiazole analogue, is an orally administered (PO) protein tyrosine kinase (PTK) inhibitor with specificity for five kinases/kinase families that have been strongly linked to multiple forms of human malignancies.(7-9) These targets include: BCR-ABL, c-Src, c-KIT, PDGFβ receptor, and EPHA2. In vivo and in vitro studies have established that dasatinib demonstrates potent antiproliferative activity in a wide spectrum of cancer cell lines/types, and early clinical results also suggest anticancer activity of dasatinib in chronic myelogenous leukemia (CML) and solid tumor patients.(10-13)
Dasatinib potently and selectively inhibits the five oncogenic PTKs/kinase families by competing with ATP for the ATP-binding sites in the kinases: Src family kinases (IC50: Src = 0.55 nM, LCK = 1.1 nM, YES = 0.41 nM, FYN = 0.2 nM); BCR-ABL (<3 nM); c-KIT (13 nM); EPHA2 (17 nM) and PDGFb receptor (28 nM) (Investigator’s Brochure, 2009). The agent was found to be less potent against unrelated PTKs and several serine/threonine kinases. Dasatinib also demonstrates potent inhibition of VEGF- and bFGF-driven proliferation of human umbilical vein endothelial cells (HUVECs), with IC50 values of 43 and 248 nM, respectively.
The Src family of protein tyrosine kinases is comprised of nine homologues that are highly conserved throughout evolution, and members of the family are ubiquitously expressed in virtually all metazoan cells, including human epithelia.(14) Platelets, osteoclasts, and neural cells are the only normal cell types known to contain high levels of Src. Src TK activity is important in the epithelia to mesenchymal transition that occurs in the early stages of invasion of carcinoma cells. (15) Although the evidence for mutational activation in epithelial cells is weak, there is clear evidence that Src expression and activity are increased at various stages in tumor development including pre-malignant epithelial changes (e.g., ulcerative colitis, Barrett’s esophagus), in primary tumors (e.g., breast, colon, ovary, bladder, lung, esophagus), and in metastatic sites (e.g., colon cancer, where activity is increased compared to a synchronous primary). The underlying epithelial cell biology implicates Src kinases in the processes of invasion, adhesion, cell motility, regulation of cell junctions, and migration. Studies have shown that focal adhesion kinase (FAK) and Src cooperate to control cell adhesion and migration through modulation of focal adhesion formation and its turnover. It was previously observed that upon acquisition of an endocrine-resistant state, MCF-7 cells possess elevated Src activity and gain a motile and invasive phenotype.(16) Increased Src TK activity in tumors may promote a tumor-invasive phenotype through both its disruption of normal cell-cell adhesion and by facilitating a motile tumor cell phenotype. This observation is supported by clinical evidence that indicates a relationship between deregulated Src TK activity and the increased invasive potential of tumor cells. Src is also involved in signaling pathways regulating survival, angiogenesis, steroid receptor activation, and growth factor receptors. Increased Src activity has been shown to correlate with disease progression, with the highest activity found in metastatic tissues. Furthermore, Src expression and activity have been linked to adverse prognosis in colorectal and prostate cancer.(17, 18)
Nonclinical Studies
Nonclinical Efficacy
Dasatinib inhibits growth of multiple BCR-ABL-dependent leukemic cell lines and also shows activity against 14 of 15 imatinib-resistant BCR-ABL kinase mutants.(19) Inhibition of CML cell lines established from patients who were resistant to imatinib therapy has also been reported (Wu et al., 2004). Dasatinib potently inhibits wild-type (IC50: 1-10 nM) and mutant (IC50: 10-100 nM) KIT kinases in M07E cells and human mast cell leukemia cell lines, respectively (Schittenhelm et al., 2006). Also of note, dasatinib selectively killed primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells.(20)
Dasatinib demonstrated antiproliferative activity in a wide-spectrum of solid tumor types, including mastocytoma, prostate, colon, breast, and rhabdomyosarcoma cell lines with IC50 values ranging from 5.4-845 nM.(8) The agent also inhibited stem cell factor-driven proliferation of three small cell lung cancer (SCLC) cell lines with IC50 values in the range of 114-220 nM and showed activity in head and neck squamous cell carcinoma and non-small cell lung cancer cell lines.(21)
When dasatinib was administered twice daily (BID) on a 5-days-on/2-days-off schedule for a total of 14 to 25 days at doses of 10-50 mg/kg/dose, in vivo antitumor activity of dasatinib was seen in prostate, colon, SCLC, and rhabdomyosarcoma xenograft models. Similarly, dasatinib was effective against K562 and imatinib-resistant K562-R human CML xenografts in SCID mice at doses as low as 2.5-5 mg/kg/day.(22) In combination with paclitaxel, dasatinib produced antitumor effects against PC3 human prostate carcinoma xenografts that were significantly better than the effects of either single agent alone (P = 0.05).(8)
Dasatinib at 20 or 50 mg/kg inhibited the T-cell proliferation response in mice following the transfer of lymphocytes from allogeneic donor mice.(8) In addition, treatment of mice with dasatinib 25 mg/kg BID inhibited the graft-versus-host response in a non-vascularized model of murine heart transplant. The 5-days-on/2-days-off regimen almost completely eliminated immunosuppressive activity in this model.
Src kinase is known to play a major role in osteoclast function. In short-term studies, dasatinib acted as a potent inhibitor of bone resorption as measured by its ability to reduce the release of 45calcium into the culture medium by fetal rat long bones in vitro (IC50 = 2 nM). Dasatinib also inhibited parathyroid hormone (PTH)-stimulated release of 45calcium in a dose-dependent manner with an apparent IC50 of 2 nM. At 5 nM, dasatinib completely blocked PTH-stimulated bone resorption in thyro-parathyroidectomized rats. The therapeutic utility of dasatinib in the treatment of cancer-related hypercalcemic syndromes has not been fully explored, and the long-term effects of dasatinib on bone physiology are also unknown.