Bicalutamide With or Without Metformin for Biochemical Recurrence in Overweight or Obese Prostate Cancer Patients (BIMET-1)
Phase: PHASE2
Conditions: Cancer of Prostate
Sponsor: Fox Chase Cancer Center

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GU-079 Bicalutamide with or without metformin for biochemical recurrence in 
prostate cancer patients (BIMET-1)
Sponsored by Fox Chase Cancer Center
Principal Investigator:
Daniel Geynisman, MD
Fox Chase Cancer Center 
333 Cottman Ave
Philadelphia, PA 19111
Phone: (215) 728-3889
Fax: (215) 728-3639
Email: Daniel.Geynisman@fccc.edu
Sub-Investigators:
Elizabeth R. Plimack, MD, MS 
Fox Chase Cancer Center
333 Cottman Ave
Philadelphia, PA 19111
Phone: (215) 728-3889
Fax: (215) 728-3639
Email: elizabeth.plimack@fccc.edu
Marijo Bilusic, MD, PhD
Asso Research Physician
NCI, 10 center Dr Bldg 10
Bethesda MD 20892
Ph: (301) 402-0576
Email: 
marijo.bilusic@nih.gov

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Statistician:
Eric Ross, PhD
Fox Chase Cancer Center 
333 Cottman Avenue
 Philadelphia, PA 19111
Phone 215-728-2724
Email: eric.ross@fccc.edu
Version Date: 01/18/2016 Amendment 1
  01/24/2017 Amendment 2
                          10/30/2017 Amendment 3
  6/20/2019 Amendment 4
                          

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D0 prostate cancer 
Stratify
1. prior therapy (surgery 
vs radiation)
Schema
Arm A 
Cycles 1-2: Observation
Cycles 3-8: Bicalutamide 50 mg 
daily continuously to end of study
Arm B
Cycles 1-2: Metformin 1000mg BID 
Cycles 3-8: Bicalutamide 50 mg daily 
and Metformin 1000 mg BID
1 Cycle = 28 days = 4 weeks. Treatment will be administered on an outpatient basis
ӿ Metformin starting dose is 500 mg BID, will be gradually increased to target dose of 
1000mg BID (see dosing table below).
Treatment ARM A
Cycles 1 – 2: Observation without treatment
Cycles 3 – 8: Bicalutamide 50 mg daily, orally, continuously to the end of study (week 32).
Treatment ARM B
Cycles 1 - 2: In order to minimize gastrointestinal discomfort, metformin dosing will be 
ramped up over a period of 2 weeks. Metformin treatment will be started at 500 mg BID 
(Dose Level -2) and increased by an increment of 500 mg daily every week +/- 2 days 
provided no grade 2 or higher gastrointestinal toxicity is noted. If grade 2 or greater 
gastrointestinal toxicity occurs during the first 4 weeks of treatment, the subject will be 
evaluated every 2 weeks until resolution of toxicity to grade 0 or 1 and, then, the metformin 
dose will be increased to the next dose level. The target dose of metformin is 1000 mg BID. 
If patient cannot tolerate higher dose, metformin will continued at maximum tolerated dose 
as listed below.
Dose level
Metformin dose
Dose Level -2 (Week 1 +/- 2 days)
500 mg twice daily
Dose Level -1 (Week 2 +/- 2 days)
500 mg breakfast / 1000 mg at bedtime
Dose Level  0  (Week 3 and later)
1000 mg twice daily
Cycles 3 – 8: Continue metformin at maximum tolerated dose (up to 1000 mg BID). Start 
bicalutamide 50 mg/daily, orally, on a continuous basis to the end of study (week 32).
RANDOMIZE

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Contents
Contents
1.0 INTRODUCTION..........................................................................................................7
1.1 Biochemical recurrence of prostate cancer .......................................7
1.2 Androgen receptor role in prostate cancer.........................................8
1.3 Clinical Experience with Metformin....................................................10
1.4 Metformin and its role in cancer..........................................................10
1.5 Metformin and prostate cancer.............................................................13
1.6 Obesity and prostate cancer.....................................................................14
1.7 Rationale and Hypothesis .......................................................................15
2.0 OBJECTIVES...............................................................................................................16
3.0 PATIENTS SELECTION............................................................................................17
3.1 Inclusion Criteria......................................................................................17
4.0 PROTOCOL MANAGEMENT...................................................................................19
4.1 Registration and Randomization Procedures..................................19
5.0 TREATMENT PLAN..................................................................................................20
5.1 Informed Consent and Consent for Tissue Collection...................20
5.2 Baseline Disease Assessment ...............................................................20
5.3 Study Treatment.......................................................................................20
5.3.1
Treatment ARM A.............................................................................................................20
5.3.2
Treatment ARM B .............................................................................................................21
5.4.1   Pill Diary...............................................................................................................................21
5.4.2
Bicalutamide.....................................................................................................................21
5.4.3
Metformin ........................................................................................................................21
5.4.4
Missed doses ....................................................................................................................21
5.5.1.
Dose Modifications for Metformin ...................................................................................22
Diagnostic Imaging:...........................................................................................................................24
General Anesthetic:..........................................................................................................................24
Any Situation Considered Medically Necessary: ...............................................................................25
5.5.2.
Dose Modifications for Bicalutamide................................................................................25
6.1 Schedule of Assessments........................................................................27
6.2 Screening.....................................................................................................28
6.3 Treatment Evaluations...........................................................................28
6.4 End of Study and Follow up...................................................................28

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7.0 MEASUREMENT OF EFFECT..................................................................................28
7.1 Definitions of Biochemical Response and Progression ...............28
7.1.4
Progressive Disease: .........................................................................................................29
7.2 Radiographic Progression.....................................................................29
7.3 Survival........................................................................................................29
7.4 Time to PSA Progression........................................................................29
7.5 Time to PSA Nadir ....................................................................................29
7.6 PSA Slope.....................................................................................................29
7.7 Symptomatic Deterioration..................................................................30
7.8 Duration of Response..............................................................................30
7.9 Quality of life (QOL).................................................................................30
8.0 TISSUE COLLECTION AND CORRELATIVE STUDIES ......................................30
8.1 Pathology Review......................................................................................30
8.2 Tissue Collection.......................................................................................30
8.2.1 Use of Tumor Blocks ................................................................................................................31
8.3 Use of Blood Samples ..............................................................................32
9.0 BACKGROUND THERAPEUTIC INFORMATION...............................................35
10.0  ADVERSE EVENTS.................................................................................................38
10.1
Definition of Adverse Experience....................................................38
10.2
Recording and Reporting Responsibilities..................................39
11.0   STATISTICAL CONSIDERATIONS.....................................................................41
11.1
Sample size.............................................................................................41
11.2  Toxicity assessment ..............................................................................43
11.1
Secondary assessments......................................................................43
11.4
Definition of Populations for Analyses..........................................43
11.5
Safety Analyses......................................................................................43
12.0  DATA SAFETY MONITORING PLAN.................................................................44
12.1
Monitoring Plan....................................................................................44
13.0 Administrative .......................................................................................................44
13.1
Data Reporting......................................................................................44
13.2
Retention of Records...........................................................................45
13.3
Study Agents...........................................................................................45
13.4
Informed Consent.................................................................................45
14.0 REFERENCES...........................................................................................................46

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1.0
INTRODUCTION
1.1
Biochemical recurrence of prostate cancer
Around 161,360 men will be diagnosed with prostate cancer in the United States in 
2017 and an estimated 26,730 will die of the disease1. About 20 to 40% of patients undergoing 
radical prostatectomy (RP)2 and 30 to 50% of patients undergoing radiation therapy (RT) at 
some time point will experience rising prostate specific antigen (PSA) following definitive 
therapy in the absence of visible metastases on imaging3, a condition known as biochemical 
recurrence (BCR)4. The definition of BCR is dependent upon the type of local therapy. 
Biochemical recurrence after RP is defined by PSA level greater than 0.2 ng/mL measured 6 - 
13 weeks after RP, followed by a confirmatory test showing a persistent PSA > 0.2 ng/mL 5. 
Biochemical recurrence after RT is defined as a PSA rise of 2 ng/mL or more above the 
nadir, regardless of whether or not a patient receives androgen deprivation therapy (Phoenix 
definition)6. The Phoenix definition has shown improved accuracy over the ASTRO 
(American Society for Radiation Oncology) definition of biochemical failure (defined as 
three consecutive PSA rises following a nadir) in predicting clinical failures and has been 
widely used in clinical practice7.
In this asymptomatic phase of the disease, the most effective management is still 
unknown since no intervention has been shown to prolong survival. Acceptable treatment 
options include: 1) salvage radiation therapy for BCR after prostatectomy; 2) salvage 
prostatectomy in selected cases after RT; 3) observation with close surveillance; 4) 
intermittent or continuous androgen deprivation therapy (ADT); or 5) enrollment in clinical 
trials.
Several retrospective studies demonstrated that early ADT has no significant effect on 
overall survival (OS) since it decreases prostate cancer-specific mortality (PCSM) but 
increases non-prostate cancer specific mortality8-10. Retrospective study by Garcia-Albeniz 
and colleagues presented at 2014 Annual ASCO Meeting used the CaPSURE registry to 
evaluate data from 2,012 patients with PSA-only relapse after radical prostatectomy or 
radiation therapy. Patients who underwent immediate ADT demonstrated no significant 
advantage in all-cause mortality (HR=0.94) or prostate cancer-specific mortality (HR=1.15). 
Estimated 5-year OS rates of 85.1% in the immediate ADT arm and 87.2% in the deferred 
ADT arm, and estimated 10-year OS was 71.6% in both arms, indicating that there may be 
no need for immediate ADT treatment in BCR patients11.
Patients with BCR have a variable clinical course: some will have indolent course 
with no impact their OS; others may have a rapid progression to radiographically apparent 
metastasis with increased risk for dying from prostate cancer. Comparison of outcomes 
demonstrated that patients with BCR have a 88% 10-year OS rate in contrast to the 93% 10- 
year OS rate in men without BCR12. In a landmark study evaluating BCR following RP, the 
median time from BCR to clinical progression was noted to be 8 years and from metastasis to 
PCSM was 5 years13, indicating that median OS from the diagnosis of BCR was around 13 
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PSA doubling time (PSADT) after the prostate cancer treatment can also be used to 
provide some insight into prognosis. A study of 432 T1-3N0M0 prostate cancer patients who 
developed BCR following definitive three-dimensional conformal radiotherapy (3DCRT) or 
intensity modulated radiotherapy (IMRT) from 1989 to 2005 demonstrated that PSADT
remains a significant predictor of clinical failure and prostate cancer specific survival. 
Immediate use of ADT in patients with PSADT of <6 months was significantly associated with 
improved prostate cancer specific survival, although the survival benefit was less apparent in 
patients with longer PSADT14.
Choueiri and colleagues reported a retrospective analysis of 3,071 men who 
underwent radical prostatectomy at Duke University (between 1988 and 2008). After a 
median follow-up of 7.4 years from the time of RP, 17.8 % men had had a BCR and 14.8 % 
had died of all causes. The median follow-up after PSA failure was 11.2 years. In men who 
experienced BCR, a PSA doubling time <6 months was associated with a significantly 
increased risk of overall death from any cause (HR = 1.55)15.
D'Amico and colleagues have suggested that men who have a BCR with a PSADT > 
15 months after RP are at minimal risk for prostate cancer metastasis or prostate cancer 
specific mortality, whereas those with a PSADT of 3 months or less are at very high risk. 
Another study of 8,669 patients with prostate cancer treated with RT (5,918 pts) or RP (2,751 
pts) found that a PSADT < 3 months was also significantly associated with prostate cancer 
specific mortality16.
A retrospective study of patients with BCR who were enrolled in four clinical trials at 
Johns Hopkins University of the non-hormonal agents: marimastat (a  matrix metalloproteinase 
inhibitor), imatinib, 
ATN-224 
(a 
copper/zinc-superoxide dismutase inhibitor) and 
lenalidomide demonstrated that changes in PSADT were prognostic for metastasis-free 
survival, which may suggest that the onset of metastasis may be delayed if an experimental 
agent is capable of significantly prolonging the PSADT17.
In summary, the value of ADT is not clear in BCR population and no study has 
shown that therapeutic intervention in this setting may improve overall survival. Further 
research is needed to determine the optimal initiation point of ADT, and whether alternative 
therapies may delay the need for ADT and prolong survival in this patient population.
1.2 Androgen receptor role in prostate cancer
Several studies demonstrated that the androgen receptor (AR) plays a crucial role in 
pathogenesis of prostate cancer18 and its progression in castration resistant disease19. AR is a 
member of the steroid receptor super family and controls expression of several genes involved 
in cell survival, differentiation, proliferation, and metabolism20. AR activation and 
overexpression are consistent findings in castration resistant clones, demonstrating the pivotal 
role of this molecular pathway21. The regulation of AR activation can be initiated by ligand-
dependent and ligand-independent mechanisms 22.

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Ligand-dependent activation is the predominant pathway in normal and castration sensitive 
prostate cancer cells. In the castrate environment it is sustained in part by overexpression and 
mutations of AR that exploit multiple mechanisms23 including AR hypersensitivity to very low 
intracellular levels of androgens24 and promiscuity for binding other steroid hormones (such 
as progesterone and estradiol) 25. In addition, prostate cancer cells develop ligand independent 
mechanisms to synthesize their own androgens by increasing the expression of genes that 
convert adrenal androgens to testosterone26. Therefore, both pathways of AR activation remain 
activated in castration-resistant disease.
Antiandrogens regulate AR function by competing for agonists binding to the AR, by 
decreasing AR phosphorylation by various growth factors27 and by preventing recruitment 
co-activators to initiate transcription of target downstream genes28. In the clinic, antiandrogens, 
such as bicalutamide, have been used in non-castrate and castration resistant prostate cancer 
patients29. There is a strong rationale for considering the AR as a therapeutic target in recurrent, 
non-castrate prostate cancer (BCR).
In the early 1990’s, single agent bicalutamide (50 mg daily) was tested as 
monotherapy in metastatic prostate cancer patients with high PSA levels. By 3 months, 20% 
of patients had a PSA decline of 85%, and by 6 months, 40% of the patients reached a 90% 
decline. Those who achieved this response had longer OS; however, this was inferior to 
complete androgen blockade (castration). Single agent bicalutamide (50 mg daily) was also 
recently tested as one arm of ECOG 2809 study in patients with BCR and results are 
pending.
In another study, single agent bicalutamide at higher dose (150 mg daily) was 
compared to combined androgen suppression with orchiectomy or Zoladex (LHRH agonist) 
and flutamide (an antiandrogen) in patients with locally advanced prostate cancer. At 6.3 
years follow-up there was no statistical difference between the two groups in time to 
progression or OS (56% mortality); however, there was a significant improvement in QOL in 
the bicalutamide arm due to improved emotional well-being, physical capacity and sexual 
interest30.
In a smaller study 41 BCR patients were treated with high-dose (150 mg) 
bicalutamide and finasteride (5α-reductase inhibitor) but no androgen deprivation therapy. 
Thirty-four of 36 evaluable patients reached a PSA nadir that represented a decline of PSA 
by 95.5%. The median time to treatment failure was 21.3 months in more advanced patients 
with median PSA values at study entry of 19.1 ng/mL. At a follow up of 3.9 years, disease 
control was comparable to castration31.
Monk et al32 used a combination of finasteride and flutamide to treat 101 BCR 
patients with rising PSA between 1 and 10 ng/mL after primary therapy. Combined 
peripheral androgen blockade regimens achieved an undetectable (<0.2 ng/mL) PSA in 40 - 
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ng/mL respectively and, achieved the nadir in 4 - 6 months. A ≥ 80% PSA decline was seen 
in 96% patients. The median time to PSA progression was 85 months. With a median follow- 
up of 10 years, the median survival time had not been reached, and the 5-year OS rate was 
87%.
The existing data supports that in BCR patients starting hormone treatment achieving 
an undetectable PSA nadir (<0.2 ng/mL) may predict for a longer survival than those whose 
PSA remains detectable. Thus, an undetectable PSA nadir promises to be the most accurate 
measure of disease response and an important endpoint for clinical trials evaluating new
approaches in hormone naïve patients. However, PSA declines ≥ 85% may also be 
considered to explore the activity of novel androgen-sparing combinations in a similar group 
and time frame.
1.3 Clinical Experience with Metformin
Metformin is a well-tolerated and inexpensive oral agent that is commonly used to 
treat diabetes mellitus and insulin resistance. It reduces serum glucose levels by inhibiting 
glycogenolysis and gluconeogenesis33. By inhibiting gluconeogenesis in the liver and 
increasing glucose uptake in skeletal muscle, metformin reduces glucose levels, increases 
insulin sensitivity and reduces hyperinsulinemia34. Metformin for the treatment of diabetes 
mellitus was approved in the 1970s in Europe and in 1995 in the United States. Its use in 
diabetes has shown to increase OS and prevent macrovascular complications better than other 
oral hypoglycemic drugs35. Metformin today has a wide variety of clinical indications: 
polycystic ovarian syndrome (PCOS), where insulin resistance is a key factor for the 
development of the metabolic disturbances. In this setting, it has a favorable effect on 
hyperlipidemia and hypertension36. It is also used in the management of the metabolic 
syndrome37 and prevention of diabetes in high-risk population38.
Its most potentially dangerous toxicity is lactic acidosis (3 cases per 100,000 patient 
years). Lactic acidosis is extremely rare if metformin use is restricted to individuals without 
any of predisposing conditions. Additional toxicities include: gastrointestinal (>1/10 - 
diarrhea, nausea, vomiting, abdominal bloating, flatulence, anorexia, metallic taste) which is 
usually transient when  treatment is started and resolving spontaneously with continued 
treatment, rash (< 1/10,000), low vitamin B12 (9% after 6 months – it is suggested that 
vitamin B12 and/or hemoglobin levels be monitored at 6 - 12 months interval), hepatic 
dysfunction (<1/10,000), TSH elevations (< 1/10,000). Modest weight loss (up to five pounds) 
is common. Hypoglycemia does not normally occur when metformin is administered
– extreme caloric restriction or excessive physical activity without adequate caloric intake 
may rarely lead to hypoglycemia.
1.4 Metformin and its role in cancer
Metformin has recently received increased attention for its potential  anti-tumor effects 
that are thought to be independent of its hypoglycemic effects. The anti-tumor effect of 
metformin it is not completely understandable and has been attributed to several mechanisms: 

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activation of LKB1/AMPK pathway, inhibition of protein synthesis, induction of cell cycle 
arrest and/or apoptosis, reduction in circulating insulin levels, activation of the immune system 
and eradication of cancer stem cells.
The major link between metformin and cancer is believed to be the AMPK upstream 
kinase LKB1 (Fig. 1). Metformin activates LKB1 (tumor suppressor protein that is mutated 
in Peutz-Jeghers syndrome and inactivated in 30 – 50% NSCLC and other tumors39) and its 
downstream target AMPK, which, in turn, suppresses the activity of the mammalian target of 
rapamycin (mTOR), a signaling pathway with a central role in cancer cell growth and cancer 
pathogenesis. AMPK is a central cellular energy sensor whose activation leads to suppression 
of  many  of  the  processes  highly  dependent  on  ample  cellular  ATP  supply,  including
gluconeogenesis,  protein  and  fatty  acid  synthesis  and  cholesterol  biosynthesis,  while 
promoting catabolic processes such as fatty acid beta-oxidation and glycolysis40.
Several studies demonstrated that activation of AMPK plays a prominent role in 
mediating the effects of metformin41, 42. Metformin decreases ATP synthesis and a rise in the 
cellular AMP:ATP ratio, effectively mimicking conditions of cellular energy stress43. While 
most research into metformin action has focused on insulin-responsive tissues, evidence 
suggests that cancer cells can initiate an AMPK-dependent energy stress response to 
metformin.
Another possible anticancer mechanism could be the decrease in circulating insulin 
levels since studies have demonstrated that type II diabetes and obesity are associated with an 
increased risk of cancer. Cancer cells express insulin as well as insulin-like growth factor 
receptors (IGF-R) and that, besides its metabolic effect, IGF-R promotes proliferation and 
metastasis44. Hyperinsulinemia may promote tumor growth by various indirect mechanisms 
too, such as proliferation of epithelial tissue, increasing bioavailability of steroid sex 
hormones and serum levels of insulin-like growth factors (IGF), as well as disrupting the 
homeostasis of adipokines, which are cytokines selectively secreted by adipose tissue and 
thought to be implicated in cancer pathogenesis. Anticancer effects of metformin have been 
demonstrated in a number of tumor model systems including the prostate, ovarian, breast, 
colorectal and endometrial carcinoma45-47.
Although typically the antitumor effect of metformin has been attributed to its ability 
to activate the LKB1/AMPK/mTOR pathway or direct inhibition of insulin/IGF-mediated 
cellular proliferation, in reality the mechanism of action of this drug is much more complex. 
Intriguingly, there are some novel data to suggest metformin may specifically target cancer 
stem cells, which are hypothesized to be resistant to conventional therapies and be a major 
reason for recurrence following radiation or chemotherapy48.
Interest in metformin as an anticancer agent began when endocrinologists noticed that 
diabetic patients taking metformin had a lower incidence of cancer. Evans et al. first described 
an association between metformin and decreased cancer  incidence in 200549. Several other 
retrospective studies showed that patients with diabetes taking metformin were less likely to 

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be diagnosed with cancer and that those who were diagnosed were less likely to die. 
Retrospective analysis of data from the ZODIAC trial, whose primary outcomes were 
diabetes-related complications, revealed that cancer related mortality was lower in patients 
taking metformin (HR 0.43; 95% CI 0.23 – 0.80)50.
Noto and colleagues reported meta-analysis with 11,117 (5.3%) cases of incident 
cancer at any site reported among 210,892 patients in 10 studies (2 RCTs, 6 cohort studies, 2 
case-control studies). The risks of cancer among metformin users were significantly lower 
than those among non-metformin users: the pooled RRs (95% CI) were 0.66 (0.49–0.88) for 
cancer mortality, 0.67 (0.53–0.85) for all-cancer incidence, 0.68 (0.53–0.88) for colorectal
cancer (n = 6), 0.20 (0.07–0.59) for hepatocellular cancer (n = 4), 0.67 (0.45–0.99) for lung 
cancer (n = 3)51.
Figure 1
Simplified schematic of the molecular mechanism of metformin action. Phospho-specific 
antibody epitopes relevant to key molecular markers are highlighted within the black 
boxes. An additional marker, stathmin 1 (STMN 1), is a surrogate marker for the signaling 
throughput via the PI3K/PTEN signaling pathway that can be monitored by 
immunohistochemistry.

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1.5 Metformin and prostate cancer
Several preclinical studies have demonstrated an effect of metformin on 
inhibiting growth of multiple cancer cell lines including prostate and breast. Ben Sahra 
and colleagues showed that metformin caused 50% decrease in cell viability in human 
prostate cancer cell lines (DU145, PC-3 and LNCaP) compared with only a modest 20% 
decrease in a normal prostate cell line (P69), suggesting that metformin may specifically 
target the prostate cancer cells45. Metformin was also reported to activate AMPK and to 
cause growth inhibition in prostate and colon cancer cells52.
Study published by Demir et al. suggested that mechanism for the anti-tumor activity of  
metformin  in  prostate  cancer  cell  lines  is  independent  of  its  anti-diabetic  effects
53.  
Metformin disrupted the AR translational MID1 regulator complex leading to release of the 
associated AR mRNA and subsequently to down-regulation of AR protein in AR positive 
cell lines. Metformin reduced levels of cyclin D in prostate cancer cells in vitro and in vivo 
and blocked cell cycle in G(0)/G(1) phase. Interestingly, this effect was independent of 
AMKP, and it was only observed in malignant cells and not normal prostate cells54.
Colquhoun and colleagues randomized LNCaP prostate cancer xenografts on a high- 
carbohydrate, high-fat (HC-HF) diet into four treatment groups; control (n=16, vehicle only), 
metformin alone (n=8), bicalutamide alone (n=9) or combined metformin and bicalutamide 
(n=8). Metformin was dissolved in cell culture medium and was administered at a dose of 50 
mg/kg. Bicalutamide was dissolved in DMSO and was also administered at a dose of 100 
μg/kg. Both drugs were administered on days 12, 14, 16, 19, 21 and 23 by intraperitoneal 
injection. Treatment with metformin and/or bicalutamide was well tolerated. Study revealed 
no significant difference in tumor volume in mice treated with metformin when compared 
with untreated control mice (P = 0.15). Conversely, mice treated with bicalutamide had 
significantly smaller tumors than untreated control mice (P = 0.02), and mice treated with a 
combination of metformin and bicalutamide had highly significantly smaller tumors than 
untreated mice (P < 0.0004). Serum PSA was significantly elevated in all treatment groups at 
the 
experiment 
termination, 
compared 
with 
levels 
obtained 
before 
treatment 
(P=0.001).Treatment with metformin did not reduce PSA levels significantly (P=0.97), 
whereas treatment with bicalutamide or the combination of metformin + bicalutamide 
significantly reduced PSA levels (34.0 and 19.0 ng/ml, respectively, P=0.002). The serum 
PSA level for the combination treatment regimen was significantly lower than that for either 
monotherapy (P = 0.002)55.
In a population-based case–control study of 1001 patients with prostate cancer and 
942 controls, metformin use was associated with a 44% risk reduction in prostate cancer 
incidence in Caucasians56. Spratt and colleagues from at Memorial Sloan-Kettering Cancer 
Center studied 2901 consecutive patients (157 diabetic patients on metformin, 162 diabetic 

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patients not on metformin, and 2582 non-diabetic patients) with localized prostate cancer 
treated with external-beam radiation therapy from 1992 to 2008. With a median follow-up of
8.7 years, the 10-yr actuarial rates for metformin, diabetic non-metformin, and nondiabetic 
patients for prostate cancer specific mortality were 2.7%, 21.9%, and 8.2% (log-rank p ≤ 
0.001)57. Surprisingly, metformin strongly decreased the clinically defined transformation to 
CRPC which at the end may improve prostate cancer specific mortality57.
Margel et al58 reported that duration of metformin treatment among diabetic men after 
a diagnosis of prostate cancer was associated with decreased prostate cancer–specific and all- 
cause mortality. This population-based observational cohort study included 3,837 men who 
were identified from several Ontario health care databases from 1997 to 2008. Eligible 
patients had to be at least 66 years of age and have been diagnosed with diabetes followed by 
a diagnosis of prostate cancer. By the end of follow-up in 2009 (median, 4.64 years), 1,343 
men had died (35%), including 291 (7.6%) from prostate cancer. Prostate cancer–specific 
mortality was decreased by 24% for each additional 6 months of metformin use after diagnosis; 
use of other antidiabetic medications did not significantly decrease prostate cancer–specific 
mortality.
Metformin as a single agent has shown modest therapeutic activity in patients with 
castration-resistant prostate cancer (CRPC). A single arm Phase II study enrolled 42 patients 
with chemotherapy naïve mCRPC treated with metformin 1000 mg twice daily until disease 
progression (defined as PSA increase 25% above baseline, progression of measurable disease 
or bone lesions, clinical progression, and start of palliative radiotherapy or death at week 12). 
36% of patients were progression-free at 12 weeks, 9.1% were progression-free at 24 weeks, 
and in two patients had ≥ 50% PSA decline. In 23 patients (52.3%) a prolongation of PSADT 
was observed. Additionally, insulin sensitivity markers improved by 26% in the first 12 
weeks of treatment. This study demonstrated that treatment with metformin is safe in non- 
diabetic patients59.
Joshua et al. reported the results of the study of 24 men (median age 64, median PSA 
6 ng/mL) with confirmed prostate cancer that were given 500 mg of metformin three times a 
day before the surgery (neoadjuvant treatment). Median duration of drug treatment was 41 
days (range 18 - 81). No grade 3 adverse events were reported, all patients underwent 
subsequent radical prostatectomy with no adverse events related to metformin. Significant 
pre-and postoperative changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), 
BMI (p<0.01). PSA reduction was not statistically significant (p=0.08). In addition, 
metformin reduced Ki67 proliferation index by 29%, compared to the baseline biopsy60 .
Despite exciting in vitro and preclinical evidence of metformin's antineoplastic 
activity, the clinical evidence has been confusing. Although metformin does not appear to be 
associated with a reduced prostate cancer risk or with a reduced risk for recurrence after 
surgery61; there is strong suggestion that metformin may reduce risk of castration resistant 
disease development and death from prostate cancer by 25% to 45%62, 63 .

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1.6
Obesity and prostate cancer
Two-thirds of the adult male population in the US is overweight or obese64 and excess 
bodyweight deregulates several pathways such insulin levels, free insulin growth factor 1 (IGF-
1), adiponectin, and sex hormones that could potentially affect prostate cancer outcomes. 
Several studies have demonstrated association between obesity and the incidence of prostate 
and other cancers65. It has been postulated that increased insulin resistance and adipokines may 
play an important role 66. Circulating levels of adiponectin and leptin in obese patients may also 
be important in prostate cancer pathogenesis67. Adiponectin levels (inhibitory adipokine) are 
reduced in obese patients, while leptin levels are increased, which at the end may promote 
prostate cancer growth68. This theory is supported by evidence showing that hyperinsulinemia 
upregulates insulin receptors in PCa cells and increases tumor growth69. Hyperinsulinemia and 
metabolic syndrome may play a role in carcinogenesis and be negatively associated with 
prostate cancer prognosis70. Increased insulin level decreases sex hormone-binding globulins, 
and causing an increase in free unbound androgens which at the end may lead to worse 
prognosis
71. In prostate cancer patients treated with RP, obesity was associated with higher-
grade tumors, a trend toward increased risk of positive surgical margins, and higher 
biochemical failure rates
72. In diabetic patients, obesity is associated with higher risk of 
high-risk prostate cancer, which is independent of the lower risk for prostate cancer in 
diabetic patients73. The lower risk for prostate cancer in diabetic patients is possibly explained 
by lower levels of testosterone in these patients74. Another retrospective study showed that the 
presence of metabolic syndrome was associated with a shorter median time to progression (16 
vs 36 months) and median OS (36.5 vs. 46.7 months) in prostate cancer patients receiving 
ADT75 .
Cao and Ma recently reported a meta-analysis of six post-diagnosis survival studies 
on 18,203 patients with 932 deaths and found that 5 kg/m(2) increase in BMI was associated 
with 20% higher prostate cancer-specific mortality. The sixteen studies followed 26,479 
prostate cancer patients after their primary treatment, a 5 kg/m(2) increase in BMI was 
significantly associated with 21% increased risk of BCR (RR: 1.21, 95% CI: 1.11-1.31 P < 
0.01). This study demonstrated that elevated BMI is associated with increased risk of 
biochemical recurrence and prostate cancer-specific mortality76. Unanswered question is does 
weight loss reduce the risk of recurrence, the development of metastases, and death from 
prostate in men with the disease?
1.7 Rationale and Hypothesis
Obesity and metabolic syndrome are prevalent among prostate cancer patients. 
Hyperinsulinemia is associated with a shorter median time to progression and median OS in 
patient with biochemical recurrence. Early ADT is frequently used in this patient population, 
with no proven benefit, which may increase mortality and morbidity.
Metformin is an inexpensive and safe drug that may have anticancer activity through 

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both insulin-dependent and insulin-independent mechanisms, which involve activation of 
adenosine monophosphate (AMP)-activated protein kinase (AMPK), inhibiting mTOR 
signaling pathway77. Recent evidence suggests activation of AMPK leads to down regulation 
of AR78 and inhibits xenograft growth of several PCa cell lines54. Metformin should work 
better in early, castrate sensitive prostate cancer since in castration resistant disease AR 
signaling is increased (through amplification, mutations, and intracellular androgen 
stimulation) which may hamper metformin's ability to inhibit cancer growth.
Bicalutamide is a non-steroidal antiandrogen, which functions by blocking the AR. It 
exerts its effect predominantly through induction of a G1/S phase arrest of the cell cycle79. 
Published preclinical data suggest the additive anticancer effects of combining metformin 
and bicalutamide in the prostate cancer patients with metabolic syndrome and possible 
synergistic activity with antiandrogens: in AR-positive cells, this effect appeared to be 
mediated by reducing proliferation rates by modulating the AR, whereas in AR-negative cells 
the combination treatment appeared to promote apoptosis.
HYPOTHESIS:
Metformin will enhance the antitumor effects of the antiandrogen bicalutamide in the 
setting of preserved testosterone, effectively delaying onset of metastases while preserving 
quality of life in overweight and obese men with castrate naïve non-metastatic prostate 
cancer with biochemical recurrence.
2.0
OBJECTIVES
2.1
Primary endpoint:
The proportion of patients with undetectable PSA (< 0.2 ng/mL) at 32 weeks with metformin 
plus bicalutamide compared to bicalutamide monotherapy.
2.2
Secondary endpoints:

The proportion of patients with PSA decline > 85% at 32 weeks with metformin plus 
bicalutamide compared to bicalutamide monotherapy.

The  time  to  PSA  progression  with  metformin  plus  bicalutamide  compared  to 
bicalutamide monotherapy.

To evaluate the time to onset of radiographic evidence of metastatic disease (rPFS) 
with metformin plus bicalutamide compared to bicalutamide monotherapy.

To characterize the PSADT changes pre-study, during treatment, and off treatment.

To evaluate the safety and tolerability of metformin in this patient population.

To evaluate QOL with metformin plus bicalutamide compared to bicalutamide 
monotherapy.

To evaluate the time to next therapy (i.e. antiandrogen or GnRH antagonist/agonist).

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2.3
Exploratory endpoints:
•
Immunogenicity of bicalutamide +/- metformin by flow cytometric analysis of T-cell 
frequency, activation status, cytokine profiles, antibody levels and analysis of sCD27 
and sCD40L
•
Evaluate circulating PSA levels and correlations with immunogenicity and/ or efficacy
3.0
PATIENTS SELECTION
3.1
Inclusion Criteria
3.1.1
Ability to understand and the willingness to sign a written informed consent.
3.1.2
Male 18 years or older.
3.1.3
Histologically or cytologically confirmed diagnosis of prostate cancer.
3.1.4
Patient must have had previous treatment with definitive surgery or radiation therapy 
or cryoablation.
3.1.5
Patient may have prior salvage therapy (surgery, radiation or other local ablative 
procedures) within 6 months prior to randomization if the intent was for cure. 
Prophylactic radiotherapy to prevent gynecomastia within 4 weeks prior to 
randomization is allowed.
3.1.6
Patient may have had prior neoadjuvant and/or adjuvant therapy (chemotherapy, 
vaccines or experimental agents) within 4 weeks prior to randomization, if the PSA 
rise and PSADT were documented after the testosterone level was > 150 ng/dL.
3.1.7
Patients may have had therapy modulating testosterone levels (such as luteinizing-
hormone, releasing-hormone  agonists/antagonists  and  antiandrogens) in the past as 
long as the testosterone level is > 150 ng/dL within 4 weeks of trial entry. Agents such 
as 5 alpha reductase inhibitors, ketoconazole, abiraterone, systemic steroids, or herbal 
supplements known to decrease PSA levels including any dose of Megestrol acetate, 
Finasteride (e.g., Saw Palmetto and PC-SPES, African pygeum extract, lycopene, 
alanine, glutamic acid and glycine, beta-sitosterol, lycopene, nettle root extract, 
quercitin, Belizian Man Vine extract, mulra puama extract and epimedium extract 
Campesterol, Beta- sitosterol, Stigmasterol, Sitostanol and Brassicasterol) are not 
permitted at any time during the period that the PSA values are being collected.
3.1.8
Patient must have hormone-sensitive prostate cancer as evident by a serum total 
testosterone level > 150 ng/dL within 12 weeks prior to randomization.
3.1.9
PSA must be < 30 ng/mL at study entry.
3.1.10 Patient must have evidence of biochemical failure after primary therapy and 

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subsequent progression. Biochemical failure is declared when the PSA reaches a 
threshold value after primary treatment and it differs for radical prostatectomy or 
radiation therapy.
●
For radical prostatectomy the threshold for this study is PSA ≥ 0.2 ng/mL
●
For radiation therapy the threshold is a PSA rise of 2 ng/mL above the nadir 
PSA achieved post radiation with or without hormone therapy (2006 RTGO- 
ASTRO Consensus definition).
●
PSA progression requires a PSA rise above the threshold measured at any 
time point since the threshold was reached.
3.1.11 PSA doubling time between 3 and 12 months. PSA calculation requires at least 
two consecutive PSA rises (PSA2 and PSA3) above the threshold PSA (at least 3 
PSA values); PSA2 and PSA3 must be obtained within 12 months of study 
entry. All baseline PSAs should be obtained at the same reference lab. Patient's 
PSA doubling time must be calculated using the following formula 
(http://www.mskcc.org/nomograms/prostate/psa-doubling-time):
3.1.12 ECOG performance status 0 to 2.
3.1.13 Ability to swallow the study drugs.
3.1.14 Subjects must have normal organ and marrow function as defined below:
●
Absolute neutrophil count > 1,000/mL
●
Hemoglobin > 10 g/dL
●
Platelets > 100,000/mL
●
Total bilirubin within normal institutional limits
●
AST(SGOT)/ALT(SGPT) < 1.5 X institutional ULN
●
Creatinine clearance > 60 mL/min/1.73 m2
●
Hgb A1c ≤ 6.5%
3.2
Exclusion Criteria
3.2.1
Evidence of metastatic disease on imaging studies (CT, x-ray, and/or bone scan).
3.2.2
Diagnosis of diabetes mellitus defined as:
●
Fasting blood glucose > 126 mg/dl or,
●
Random blood glucose > 200 mg/dl
●
Hemoglobin A1C > 6.5%

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3.2.3
Need for treatment with any conventional modality for prostate cancer (surgery, 
radiation therapy, and hormonal therapy).
3.2.4
Treatment with any investigational drug 30 days prior to randomization.
3.2.5
Radiation therapy within prior 6 months (prophylactic radiotherapy to prevent 
gynecomastia within 4 weeks prior to randomization is allowed).
3.2.6
Known hypersensitivity to metformin.
3.2.7
Prior history of lactic acidosis.
3.2.8
Any history of myocardial infarction in the past 12 months.
3.2.9
Subjects who consume more than 3 alcoholic beverages per day.
3.2.10 Subjects with serious intercurrent illness, including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia, or other nonmalignant medical or psychiatric illness that is 
uncontrolled or whose control may be jeopardized by the complications of this 
therapy or may limit compliance with the study requirements (at the discretion of the 
investigator).
3.2.11 Patient with previous or concurrent malignancy. Exceptions are made for patients 
who meet any of the following conditions: Basal cell or squamous cell carcinoma of 
the skin or prior malignancy that has been adequately treated and patient has been 
continuously disease free for ≥ 2 years.
3.2.12 Subjects currently treated with metformin and/or bicalutamide or who have been 
treated with metformin and/or bicalutamide in the past 6 months.
3.2.13 Subjects who have taken 5a-reductase inhibitors (finasteride or dutasteride), saw 
palmetto, or PC-SPES within the last 6 weeks are ineligible. Subjects will be eligible 
for the study after the wash out period of 6 weeks.
4.0
PROTOCOL MANAGEMENT
4.1 Registration and Randomization Procedures
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing the Investigator-Sponsored Research Unit (ISRU) at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study centrally 
once the following items have been received by email:

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
Completed registration form 

Consent and HIPAA signature pages 

Eligibility checklist
Following registration, participants must begin protocol treatment within 7 calendar 
days of registration.  Issues that would cause treatment delays must be discussed with 
the Sponsor-Investigator.  If a registered participant does not receive protocol therapy 
following registration, the participant will be recorded as withdrawn from study.  The 
Study Monitor must be notified as soon as possible if a participant does not begin 
protocol treatment as scheduled. For additional registration questions, please email 
FCCC.MONITOR@fccc.edu or call (215) 728-5544.
The FCCC ISRU will notify the site by email once registration is confirmed and the 
sequence number has been assigned.  Participants must be registered and have received 
a sequence number prior to the initiation of treatment.  
Exceptions to the current registration policies will not be permitted. 
5.0
TREATMENT PLAN
5.1
Informed Consent and Consent for Tissue Collection
Prior to study entry, all patients must sign inform consent. All patients will be 
presented with the option to donate a biopsy specimen for research purposes, and 
consent for this will be documented separately within the informed consent.
5.2
Baseline Disease Assessment
Imaging will be performed as described in the Study Calendar (Section 6.0).
5.3
Study Treatment
Upon initiation of treatment, both agents will be administered orally at the assigned 
doses and schedules. One cycle = 28 days = 4 weeks. Treatment will be administered 
on an outpatient basis.
5.3.1
Treatment ARM A
Cycles 1 – 2: Observation without treatment
Cycles 3 – 8: Bicalutamide 50 mg daily, orally, continuously to the end of 
study (week 32).
5.3.2
Treatment ARM B
Cycles 1 - 2: In order to minimize gastrointestinal discomfort, metformin 
dosing will be ramped up over a period of 2 weeks. Metformin treatment will 

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be started at 500 mg BID (Dose Level -2) and increased by an increment of
500 mg daily every week +/- 2 days provided no grade 2 or higher 
gastrointestinal toxicity is noted. If grade 2 or greater gastrointestinal toxicity 
occurs during the first 4 weeks of treatment, the subject will be evaluated 
every 2 weeks until resolution of toxicity to grade 0 or 1 and, then, the 
metformin dose will be increased to the next dose level. The target dose of 
metformin is 1000 mg BID. If patient cannot tolerate higher dose, metformin 
will continued at maximum tolerated dose as listed below.
Dose level
Metformin dose
Dose Level -2 (Week 1 +/- 2 days)
500 mg twice daily
Dose Level -1 (Week 2 +/- 2 days)
500 mg breakfast / 1000 mg at bedtime
Dose Level  0  (Week 3 and later)
1000 mg twice daily
Cycles 3 – 8: Continue metformin at maximum tolerated dose (up to 1000 mg BID). 
Start bicalutamide 50 mg/daily, orally, on a continuous basis to the end of study (week 32).
5.4      Guideline for Study Medication Administration
5.4.1   Pill Diary
A blank pill diary (Appendix I) will be provided to the patient by the study 
coordinator at cycle 1 and at each subsequent visit, and a completed pill diary should 
be returned by the patient at Day 1 of cycle 2 and each subsequent cycle.
5.4.2
Bicalutamide
Bicalutamide will be self-administered by the patient once daily. It may be taken with 
or without food. The tablet should be taken at approximately the same time every day. 
Bicalutamide and metformin may be taken together.
5.4.3
Metformin
Metformin will be taken at the assigned dose twice daily. Metformin is administered 
orally, with food. Bicalutamide and metformin may be taken together.
5.4.4
Missed doses
Patients who forget to take their scheduled dose of study drug should be instructed 
not to make up the missed dose. Missed doses of study drug should be recorded in 
the patient’s study record.
5.5
Dose Modifications

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All toxicities should be graded according to the Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE). Dose modifications will  be based on the 
highest grade since the prior dose and will be performed as outlined below depending on 
the type and severity of the toxicity encountered, provided that the criteria have not been 
met for subject withdrawal from study. Patients will be withdrawn from the study if they 
fail to recover to CTCAE grade 0-2 (or within 1 grade of starting values of pre-existing 
laboratory abnormalities) from a treatment related toxicity within 4 weeks. Treatment may 
be delayed no more than 4 consecutive weeks to allow recovery from toxicity or the patient 
will be removed from the study. Dose modifications are not necessary for Grade 1 or 2 
toxicities. The reason for dose modification, delay, and missed doses must be detailed in the 
source document. Dose re- escalation will not be allowed during this study.
5.5.1. Dose Modifications for Metformin
The major toxic effects of metformin which limit dose are gastrointestinal (nausea, 
abdominal bloating, diarrhea). During the ramp-up period, subjects experiencing 
gastrointestinal symptoms should be encouraged to take tablets with food. If no 
improvement, subjects should try taking study medication every other day for two 
weeks, once per day for two weeks and then twice per day thereafter. Subjects not 
tolerating study medication after this approach may go off study treatment but 
Investigators are urged to re-challenge willing subjects 4 weeks later. Dose 
adjustments, for reasons of toxicity, will be as in the tables below. (Please note that 
none of the recommended dose adjustments require splitting of study medication 
pills. Pills are not to be split or crushed, prior to taking, for any reason.) Breaks of up 
to 4 weeks consecutively or 8 weeks overall are allowed to ascertain the cause of the 
adverse events.
Gastrointestinal Toxicity
Toxicity / Adverse Event
Grade
Investigator Action
Gastrointestinal Toxicity of any type
Grade 1
Patient should be encouraged to remain on full dose. If patient is 
unwilling, stop study treatment for one week. For subjects who were 
unwilling to remain on full dose, after one week without study drug, 
follow the ramp-up procedure. If Grade 1 symptoms persist or recur 
during the ramp-up or at full dose and the patient is unwilling to continue, 
follow instructions for Grade 2 toxicity.
Nausea 
Distension/Bloating 
Diarrhea 
Gastrointestinal - Other
Grade 2 
(or higher)
Reduce to 500 mg BID for one week. If symptoms resolve or are Grade 1 
only, after one week, resume full dose (1000 mg BID).
If symptoms persist or recur at Grade 2 or higher, stop study treatment 
for 4 weeks, then resume study treatment as follows:
Re-start study drug according to original ramp-up schedule. If toxicity 
persists or recurs, the study drug should be adjusted to the maximum 
dose that is tolerated with Grade 1 toxicity or lower. A second attempt to 
increase to full dose should be made 4 weeks later and if the full dose is 
not tolerated at that time, the maximum tolerated dose should be used for 
the remainder of the study.

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Hepatic dysfunction*
(bilirubin   >   ULN   except   for   Gilbert’s 
Disease)
Grade 1 
(or greater)
Hold study drug for up to 4 weeks. If bilirubin returns to normal within 
that time frame, begin 500 mg BID for 4 weeks, then 1000 mg BID.
Hepatic dysfunction*
AST or ALT=1.8- 3.0 X ULN
Repeat AST & ALT in 2 weeks. If either AST or ALT > 1.8 X ULN, 
continue at discretion of Investigator, monitoring AST & ALT every two 
weeks until both < 1.8 X ULN – then resume annual testing.
If Investigator decides to stop medication, resume once AST &ALT < 1.8 
X ULN, starting with 500 mg BID for 4 weeks, then increasing to 2 tablets 
per day with annual AST & ALT assessments
Hepatic dysfunction* 
AST or ALT > 3.0 X ULN
Hold study drug.
Repeat LFTs in 2 weeks.
If AST and ALT < 1.8 ULN, resume medication.
Resumption involves 500 mg BID for 4 weeks, then increase to 1000mg 
BID per day with resumption of protocol specified monitoring if both AST 
and ALT remain at < 1.8 x ULN.
If repeat AST and ALT are 1.8-3.0 x ULN, follow steps as described in 
section above.
If AST and/or ALT > 3.0 x ULN, initiate workup for liver disease.
If  AST  or  ALT=1.8-3.0  resume  medication  at  the  discretion  of  the 
investigator.
Renal dysfunction 
Creatinine > 115 μmol/L
1.3 mg/dL
Hold study drug for up to 4 weeks.
After resolution of event, use ramp-up schedule.
Clinical  diagnosis  of  congestive  heart 
failure
> Grade 3
Hold study drug for up to 4 weeks.
Re-start may be considered if underlying condition (e.g. acute MI) has 
resolved. If Metformin is started after CHF, the ramp-up schedule should 
be used. Do not re-start if symptoms persist or ongoing treatment of CHF 
is required.
Acidosis
(Lactate > 5.0 mM) 
(pH < 7.3)
Grade 3
Stop study drug and do not re-start. 
Report as a serious adverse event.
Anemia
Hgb < 110 or MCV > 105
> Grade 1
Perform CBC and serum B12 level. Initiate anemia workup if cause of 
anemia not apparent. Continue at full dose. (Treatment is not held for 
anemia regardless of toxicity grade.)
Skin Reactions
Major  –  generalized  urticaria,  bullous 
rashes, exfoliative dermatitis
Generalized
Stop study drug and do not re-start

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Stevens Johnson Syndrome 
Localized
Localized
Hold study drug for up to 4 weeks if possibly, probably or definitely related 
to study drug. When rash clears, 500 mg BID per day for 4 weeks, then 
1000 mg BID per day – if rash recurs, and is thought to be possibly, 
probably or definitely related to study medication, discontinue study 
medication.
Hospitalization for any reason
Hold study drug for up to 4 weeks. The Investigator is to determine when it 
is safe to re-start. The drug should be re-started using a schedule (if the 
hospitalization resulted in discontinuation of the drug for 2 weeks or longer. 
If the discontinuation of the drug was less than 2 weeks, the drug should be 
re-started at full dose without a ramp-up.
* Be alert to signs of acidosis; protocol specific biochemistry should be checked 
annually. If subject develops malaise, nausea, dark urine, jaundice or right upper 
quadrant pain, study medication should be stopped until biochemistry is performed. 
Medication should be resumed according to the algorithms above (if first 
biochemistry results are normal, resume immediately at full dose)
Other Situations
Diagnostic Imaging:
If the subject is scheduled for any CT scans requiring intravenous contrast 
material, metformin should not be taken for 24 hours prior to the investigation 
or for 48 hours after the procedure. (This does not include contrast used for 
MRI or nuclear medicine scans, including MUGA). Study medication will 
then be resumed at full dose (without ramp-up) provided there is no 
concern about renal function. If there is concern about renal function, 
creatinine should be checked prior to resumption of study medication.
General Anesthetic:
If general anesthetic is required for surgery, study drug should not be taken 
on the morning of surgery or for 48 hours after anesthetic and surgery. 
Study medication will then be resumed at full dose (without ramp-up) 
provided there is no concern about renal function. The drug is restarted at 
full dose if the duration of interruption was less than 2 weeks. If the duration 
of drug interruption was more than 2 weeks, it should be restarted using a 4 
week ramp-up schedule (one caplet per day for 4 weeks, then two caplets per 
day). If there is concern about renal function, creatinine should be checked 
prior to resumption of study medication.
Any Situation Considered Medically Necessary:
Study medication may be held in any situation which the Investigator considers it 
medically necessary, for up to 4 weeks.
5.5.2. Dose Modifications for Bicalutamide
Not allowed. In case of CTCAE grade 3 or 4 transaminase elevation, bicalutamide 
will be stopped until the event resolved to Grade 1 or less.

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5.6
Duration of Therapy
In the absence of treatment delays due to adverse events, treatment may continue for 
8 cycles (32 weeks) or until one of the following criteria applies:
•
Disease progression
•
Intercurrent illness that prevents further administration of treatment,
•
Unacceptable adverse event(s)
•
Patient decides to withdraw from the study
•
General  or  specific  changes  in  the  patient’s  condition  render  the  patient 
unacceptable for further treatment in the judgment of the investigator.
5.7
Medication Compliance
At each study visit, patients should be instructed on the proper dosing regimen. Any 
missed doses should be documented in the patient's study record. Patient should be 
instructed not to make up any missed doses.
5.8
Concomitant Medications and Treatments
All concomitant medications received within 28 days before the first dose of study 
medication and 30 days after the last dose of study medication will be recorded in the 
patient study records, including all prescription, over-the-counter, herbal 
supplements, and intravenous medications and fluids. Any changes to the 
concomitant medication regimes should be recorded throughout the study.
5.9
Duration of Follow-up
All patients will be followed for response during 32 weeks, and followed for survival, 
adverse events, and disease status every 12 months (+/- 2 months) for up to 5 years from 
end of treatment. Any patients who experience adverse events should be followed until 
one of the following occurs:
Resolution of the adverse event to ≤ Grade 1 or baseline severity.
Determination that the adverse event is stable and will not resolve.
Initiation of another anti-cancer treatment.

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6.1
STUDY PROCEDURES
6.1
Schedule of Assessments
A Cycle is defined as 4 weeks. Patients will be evaluated according to the 
schedule in Table 1.
Table 1. Schedule of assessments
1.
Physical examinations, blood tests must be performed within 2 weeks of treatment.
2.
Evaluation is scheduled Day 1 of each cycle +/- 2 days to allow for logistical issues.
3.
Vital signs include temperature, pulse, respiratory rate, and blood pressure
4.
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, 
potassium, phosphorous, magnesium, total protein, SGOT, SGPT, sodium
Treatment cycles2
Assessment
Screening1
Cycle 
1
Cycle 
2
Cycle 
3
Cycle 
4
Cycle 
5
Cycle 
6
Cycle 
7
Cycle 
8
Off 
Treatment7
F
ollo
w 
Up9
Informed consent
x
Tissue collection consent
x
Demographics
x
Medical history
x
Concomitant Medications
x
x
x
x
x
x
x
x
x
Review of Systems
x
x
x
x
x
x
x
x
x
Physical exam2
x
x
x
x
x
x
x
x
x
Vital signs3
x
x
x
x
x
x
x
x
x
Adverse event recording
x
x
x
x
x
x
x
x
X
Height
x
Weight
x
x
x
x
x
x
x
x
x
x
ECOG PS
x
x
x
x
x
x
x
x
x
CBC with differential6
x
x
x
Serum Chemistry4,6
x
x
x
x
x
X
x
x
x
Fasting Lipids5,6
x
x
x
PSA6
x
x
x
x
x
x
X
x
x
x
Testosterone6
x
x
x
x
x
x
X
x
x
x
HgbA1c
x
x
x
Vitamin B12
x
x
CT CAP with IV contrast8
x
Bone scan*
x
Research blood
x
x
x
Research blood, optional
X
X
X
FACT – P, version 4
x
x
Survival & disease status9
X

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5.
Cholesterol, LDL, HDL, Triglycerides.
6.
All Labs (CBC, chemistries, fasting lipids, PSA, and testosterone) may be drawn up to 3 days prior to day 
1 if site is unable to obtain results on day of treatment.
7.
Off treatment evaluation should be scheduled at week 33 +/- 2 days to allow for logistical issues.
8.
At physician discretion, a Chest x-ray can be done in place of a Chest CT at screening. Repeated bone or CT scans 
can be ordered during treatment if clinically indicated.
9.
Follow up by telephone will occur once annually for 5 years, starting a year after the off-treatment visit +/- 2 months.
6.2
Screening
All patients must undergo pre-treatment evaluations. Pre-treatment evaluations will 
be used to determine the patient’s study eligibility and will include a history and physical 
(including height and weight), ECOG performance status score, vital sign measurements, 
CBC with differential and platelet counts, and serum chemistry profiles. Imaging studies for 
baseline tumor assessment will be performed within 6 weeks of the initiation of therapy. 
Patients must sign an informed consent form prior to undergoing protocol-specific 
evaluations (prior imaging studies are allowed in order to decrease radiation exposure) and 
receiving treatment. Patients may be re-screened if they previously failed the pre-treatment 
evaluation. Rescreening must occur 3 months or more from last screening and a maximum of 2 
re-screenings are allowed.
6.3
Treatment Evaluations
Patients will be examined by the treating physician or designee on day 1 of each cycle 
prior to treatment. This examination will include a physical exam, toxicity assessment, 
concomitant medication review, and performance status. The physical exam must not occur 
more than 14 days prior to day 1 treatment. Chemistries, PSA, testosterone will be performed 
every 4 weeks, prior to each cycle. All required labs (such as CBC, chemistries, lipids, PSA, 
testosterone, etc) may be drawn up to 3 days prior to day 1 if site is unable to obtain results 
on day of treatment.
6.4
End of Study and Follow up
Patients will have an evaluation and physical examination when they are taken off 
study treatment or complete study treatment (week 33). The reason for ending study 
treatment must be described in the source document and in OnCore. This evaluation will 
include a physical examination (including weight and vital signs), ECOG performance status 
score, CBC with differential and platelet counts, serum chemistry profiles, PSA, testosterone, 
HgbA1c, fasting lipids, research blood collection and toxicity assessment. Patients will be 
contacted every 12 months (+/- 2 months) to collect survival information, disease status, and 
the presence of persistent AEs for the next 5 years.
7.0
MEASUREMENT OF EFFECT
7.1
Definitions of Biochemical Response and Progression
7.1.1
Complete Response: PSA <0.2 ng/mL confirmed on two consecutive 

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additional determinations taken at least 4 weeks apart.
7.1.2
Partial Response: A reduction in PSA ≥ 50% from baseline without 
evidence of clinical or radiographic progression confirmed on two 
consecutive additional determinations taken at least 4 weeks apart.
7.1.3
Stable Disease: Patients who do not meet the criteria for response 
(CR or PR) or serological progression for at least 3 months (90 days) 
will be categorized as having stable disease.
7.1.4
Progressive Disease:
1) For patient who achieved a ≥ 50% decline in PSA, progression is 
defined as an increase in PSA value by 50% above baseline or nadir 
(whichever is lowest), confirmed by a second PSA rise at least two 
weeks later. The PSA rise must be at least 5 ng/mL. Changes in PSA 
below 5 ng/mL will not be considered assessable for progression.
2) For patients with an undetectable PSA nadir (< 0.2 ng/mL), 
progression is defined as a PSA rise to the detectable range (detectable 
PSA is ≥ 0.2 ng/mL) confirmed by a second PSA rise at least 2 weeks 
later.
3) For patients whose PSA has not decreased by 50%, progression is 
defined as an increase in PSA value ≥ 50% of baseline (on trial) or 
nadir PSA, whichever is lowest, confirmed by a repeat PSA at least 2 
weeks later. The PSA must have risen by at least 5 ng/mL.
7.2
Radiographic Progression
The appearance of new lesions on examination or radiographs (CXR, CT 
scan, MRI scan, or bone scan) with or without a concurrent increase in serum 
PSA from baseline.
7.3
Survival
Survival will be measured from the date of randomization.
7.4
Time to PSA Progression
Time to PSA progression is defined as time from randomization to first 
confirmed rise in PSA (or development of clinical progression) meeting 
progressive criteria after starting bicalutamide treatment.
7.5
Time to PSA Nadir
Time to PSA nadir is defined as the time from randomization to the date that 
PSA nadir is documented. PSA nadir is defined as the lowest PSA value 
achieved after registration or baseline PSA, whichever is lowest.
7.6
PSA Slope

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The change in PSA will be graphically depicted and a PSA slope calculated. 
The change in PSA slope (and PSADT) pre-study, during-study, and off-study 
will be determined to see if the treatments have any disease modifying effects, 
especially in those patients experiencing stable disease. This end-point is 
exploratory, but may help to interpret PSA response.
7.7
Symptomatic Deterioration
Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be classified as having symptomatic deterioration.
7.8
Duration of Response
The period measured from the time that PSA criteria are met for complete or 
partial response (whichever status is recorded first) until the first date that 
progressive disease is documented.
7.9
Quality of life (QOL)
Quality of life will be assessed during the screening visit and after the study 
completion using The Functional Assessment of Cancer Therapy-Prostate 
(FACT-P) questionnaire. It is a relevant, worldwide tool used for assessing the 
health-related quality of life in men with prostate cancer.
8.0
TISSUE COLLECTION AND CORRELATIVE STUDIES
8.1 Pathology Review
There will be no central pathology review for this study. Patient must have 
diagnosis of prostate cancer histologically confirmed at the participating 
institution.
8.2Tissue Collection
The collection of a representative block of the diagnostic tumor tissue (if 
available) is an important part of this trial; however, the participation of 
subjects is optional. Blocks will be carefully banked as part of the Fox Chase 
tissue/tumor bank. Tumor blocks will be the preferred material to collect, as 
one of the objectives will be to create tissue micro arrays. These will optimize 
the amount of tissue available to investigators and permit the preservation of 
the tumor block submitted. If, at any time, the submitting hospital requires the 
block to be returned for medical or legal concerns, it will be returned by 

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courier on request.
The tissue may be used by researchers now or in the future to better understand 
the nature of prostate cancer and how patients respond to treatment. Samples 
will be used for research purposes only and will not be sold. Patients will not 
be identified by name. The only identification of tissue will be by a patient 
study number assigned at the time of randomization to the trial the surgical/ 
histology number and/or patient initials. Material issued to
researchers will be anonymized and only identified by a coded number. 
Diagnostic pathology reports are received as part of the supporting 
documentation required for this trial. Testing for hereditary genetic defects 
predisposing to malignant disease will not be carried out without the 
expressed consent of the subject. All subjects on whom a diagnostic tumor 
block is collected will be aware of this retrieval and will have given their 
consent.
8.2.1 Use of Tumor Blocks
As part of the embedded correlative science for the protocol, the following 
research is planned using archival tissue samples collected and banked at the 
time of study entry:
a) Insulin Receptor (IR)
We plan to quantify IR expression by IHC and correlate results with 
clinical outcomes.
b) LKB1
We plan to quantify LBK1 expression by IHC and correlate results with 
clinical outcomes. LKB1 expression is key to the ability of metformin to 
affect AMPK activity within tumors and to suppress the growth- 
promoting outputs of this signaling pathway (i.e. mTOR-regulated 
protein translation). LKB1 expression is essential for direct (insulin 
independent) effects of metformin.
c) Phosphoantibody Markers of Activation of Key Signaling Pathways 
Expression of IR and LKB1 will be indicative of the capacity of tumor cells to 
respond to indirect (insulin and IR mediated) and direct (insulin independent,   
LKB1   mediated)   effects   of   metformin   respectively, however, the 
expression of these factors cannot distinguish whether the pathways  underling  
these  responses  are  actually  activated.  Multiple other genetic factors may alter 
pathway activation. As a result, activation markers of these pathways [PI3K 
(STMN1), PKB/Akt (P-PKB/Akt,) mTOR (P-4E-BP1) and IRS-1 (P-IRS-1)] 
will be evaluated as predictors of metformin benefit. If one or more of these 
biomarkers are activated at prostate  cancer  diagnosis,  it  is  predicted  that  
metformin  benefit  is possible. If none of these pathways is activated, it is 
predicted that metformin  benefit  will  not  be  seen,  regardless  of  IR  and/or  

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LKB1 expression.
8.3Use of Blood Samples
Correlative studies will be an integrated component of the clinical trial. Investigations 
of fasting glucose and insulin levels at baseline, 9 weeks post randomization and at 
the end of study treatment will be mandatory and will explore the indirect insulin- 
mediated effect of metformin on protocol defined outcomes. Other measurement will 
include, but not limited to IGF1 level Inhibition of the downstream targets of the 
mTOR pathway: 4E-BPI and p70S6K1, IGF-1/IGFBP-3 (observed on peripheral 
blood mononuclear cells (PBMCs).
a) Genomic/Gene Expression Profile Predictive of Metformin Benefit Large-scale 
genomic studies over the past two decades have identified numerous recurrent 
genetic events in prostate cancer.  More recent studies are focusing on building a 
comprehensive, genome-wide understanding of various types of prostate cancer. 
We plan to use such analyses to search for a genomic/gene expression profile 
predictive of metformin benefit. In the case of observed metformin benefit, we 
will perform comprehensive genomic/gene expression analysis of peripheral 
blood and available tumor material. Considering rapid technical advances in the 
genomic analysis arena, at the time of analysis, we will choose the most 
appropriate methodology to delineate the genetic/gene expression predictors of 
metformin benefit.
b) Blood Collection and Analysis Investigation of a core group of blood variables 
(at baseline, 9 weeks after enrolment and at the end of treatment) and tumor related 
factors (at diagnosis) will be examined as predictors of metformin benefit in this 
trial is outlined below. We will also collect additional samples that will allow us 
to examine a broader array of both prognostic and predictive factors in future 
work. The blood collection for fasting glucose and insulin is a mandatory part 
of the baseline, 9 weeks and end of treatment measurements. 
After an overnight fast of at least 12 hours, participants will provide the following 
blood specimens: 1 tube for immediate glucose analysis (performed according to 
established institutional practice), light green topped tubes (containing lithium 
heparin - for plasma), red topped tubes (for serum) and lavender topped tube (for 
DNA). Lavender topped tubes for DNA should be collected even for patients 
who consent to blood banking but refuse genetic testing. DNA may be used to 
study gene expression without fitting the definition of genetic testing. The 
green topped tubes will be centrifuged within half an hour of collection and the 
plasma collected frozen immediately in 1 ml aliquots at -80°C. The red topped 
tubes will sit for 30 minutes at room temperature and then be centrifuged and 
the collected serum frozen immediately in 1 ml aliquots at -80°C. Lavender topped 
tubes (whole blood in EDTA) will be collected and frozen at -80°C in 1 ml 
aliquots for subsequent thawing and DNA extraction. Specimens will be stored at 

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participating centers immediately after collection and then shipped to a central 
laboratory, frozen on dry ice, in batches of 10 sets or more (1 set = entire 
blood collection at one patient visit), for subsequent storage and ultimate analysis. 
Our plan to collect lymphocytes for DNA at both baseline and at the end of 
study (week 33) will provide the necessary sample to evaluate not only 
germline DNA but also potential changes in DNA methylation as a result of the 
metformin intervention.
In addition to blood samples collection listed above additional blood samples will 
be collected at the NCI site for immune assessments in some patients (exploratory): 
6 (10mL) green top sodium heparin tubes for PBMC and 2 (8mL) SST tubes for 
serum samples) at baseline, week 9 and week 32 (end of study). Immune 
assessments will be performed at the Laboratory of Tumor Immunology and 
Biology at the NCI’s Center for Cancer Research (CCR) and will include flow 
cytometry-based and serum assays. Samples will be analyzed in batches after 
enrolling all patients in order to ensure best laboratory practices and quality data. 
From samples acquired the following assays will be performed: 
1
Analyses of PBMCs: PBMCs separated by Ficoll-Hypaque density 
gradient centrifugation, will be analyzed for changes in standard 
immune cell types (CD4 and CD8 T cells, natural killer [NK] cells, 
regulatory T cells [Tregs], myeloid-derived suppressor cells 
[MDSCs], and dendritic cells) as well as 123 immune cell subsets, as 
described elsewhere (Lepone et al 2016)80.
2
Analyses of soluble factors: Sera will be analyzed pre- and post-
therapy for the following soluble factors: sCD27 and sCD40 ligand.
3
Additional assays: Blood samples may be used for additional research 
studies, which may include phenotypic and functional analysis of 
immune-cell subsets (such as CD4 and CD8 T cells, NK cells, Tregs, 
and MDSC), T cell clonality, circulating tumor cells, RNA and 
proteomic analyses, and analyses of cytokines (such as IFN-γ, IL-10, 
IL-12, IL-2, IL-4, etc.), chemokines, antibodies, tumor-associated 
antigens, and/or other markers.
c) Insulin (plasma)
Our core analyses will explore the indirect, insulin mediated, effect of metformin 
as a predictor of invasive disease free survival (primarily), overall survival and 
prostate cancer free interval, including an evaluation of both baseline fasting 
insulin (primarily), change in insulin over 9 weeks (secondarily) and at the end 
of treatment. This primary focus on insulin reflects the recognition that insulin 
at diagnosis is a prognostic factor in prostate cancer, and it reflects the major 
impact metformin has on insulin levels; our hypothesis is that higher insulin 

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level at baseline will predict metformin benefit in the overall study population. 
Additionally, in exploratory analyses we will examine the relationship between 
changes in insulin level during the first 6 months of metformin administration.
d) Glucose (plasma)
We plan to examine whether baseline glucose predicts metformin benefit 
independent of insulin or whether glucose modifies effects of insulin as a 
predictor of metformin benefit. We will also investigate Homeostasis Model 
Assessment (HOMA), an empirically derived estimate of insulin sensitivity 
calculated from a single measure of fasting insulin and glucose that correlates 
well with the gold standard frequently sampled intravenous  glucose tolerance 
test, as a predictor of metformin benefit, focusing on whether it provides 
additional prediction beyond insulin alone
Research Blood 
Samples Taken 
at Baseline and 
Again at 9 
weeks and at 
End of Study 
Treatment
One Tube (7 ml) 
(1.4 teaspoons)
Light Green Top 
Tubes
(3 x 4.5 ml)
(2.7 teaspoons)
Red Top Tube 
(2 x 6 ml)
(2.4
teaspoons)
Lavender Top Tube (1 
x 6 ml)
(1.2 teaspoons)
Sera for Fasting 
Glucose
(done locally 
according to 
institution’s 
procedures & 
mandatory)
Insulin
(done centrally & 
mandatory) 
Plasma for storage 
for future research 
(optional)
Serum for 
storage for 
future research 
(optional)
DNA extraction 
(done centrally & 
optional)
Lavender topped tubes for 
DNA should be collected 
even for patients who 
consent to blood banking 
but refuse genetic testing. 
DNA may be used to study 
gene expression without 
fitting the definition of 
genetic testing.
Research Blood 
Samples Taken 
at Baseline and 
Again at 9 
weeks and at 
End of Study 
Treatment
Green Top 
Sodium Heparin 
tubes (6 x 10 
ml) 
SST tubes (2 x 
8 ml) 

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PBMC for immune 
assessments
(done at the 
NCI & 
mandatory)
Serum samples for 
soluble factor 
analyses
(done at the NCI & 
mandatory)
TOTAL VOLUME DRAWN = 114.7 ML 
9.0
BACKGROUND THERAPEUTIC INFORMATION
9.1 Metformin (Please refer to the package insert for more comprehensive 
information.)
9.1.1 Availiability: Metformin is commercially available
9.1.2
Other Names: Glucophage; Glumetza; 1,1-Dimethylbiguanide; 
Metiguanide; 
Diabex; 
Dimethylbiguanide; 
Metforminum; 
Diabetosan; 
Fluamine: a commercially available agent.
9.1.3 Chemical Name: 3-(diaminomethylidene)-1,1-dimethylguanidine
9.1.4 Molecular Formula: C4H11N5
Metformin HCl is a white crystalline powder soluble in water and 95% ethyl 
alcohol. It is practically insoluble in ether and in chloroform. Melting Point: 
218-220o C
9.1.5 Mode of Action:
Metformin HCl is a biguanide derivative producing an antihyperglycemic 
effect which can only be observed in man or in the diabetic animal and only 
when there is insulin secretion. Metformin, at therapeutic doses, does not 
cause hypoglycemia when used alone in man or in the non-diabetic animal, 
except when using a near lethal dose. Metformin has no effects on the 
pancreatic beta cells. The mode of action of metformin is not fully understood. 
It has been postulated that metformin might potentiate the effect of insulin or 
reduce hepatic gluconeogenesis. Metformin absorption is relatively slow and 
may extend over about 6 hours. The drug is excreted in urine at high renal 
clearance rate of about 450 mL/min. The initial elimination of metformin is 
rapid with a half-life varying between 1.7 and 3 hours. The terminal 
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with a halflife between 9 and 17 hours. Metformin is not metabolized. Its 
main sites of concentration are the intestinal mucosa and the salivary glands. 
The plasma concentration at steady-state ranges about 1 to 2 mcg/mL. Certain 
drugs may potentiate the effect of metformin HCl, particularly sulfonylurea 
type of drugs in the treatment of diabetes. The simultaneous administration of 
these two types of drugs could produce a hypoglycemic reaction, especially if 
they are given in patients already receiving other drugs which, themselves, 
can potentiate the effect of sulfonylureas. These drugs can be: long-acting 
sulfonamides, 
tubercolostatics, 
phenylbutazone, 
clofibrate, 
monoamine 
oxidase inhibitors, salicylates, probenecid and propanolol. In healthy 
volunteers, the pharmacokinetics of propranolol and ibuprofen were not 
affected by metformin when co-administered in single-dose interaction 
studies.
Metformin is negligibly bound to plasma proteins and is, therefore, less likely 
to interact with highly protein-bound drugs such as salicylates, sulfonamides, 
chloramphenicol, and probenecid, as compared to sulfonylureas, which are 
extensively bound to serum proteins.
Human Toxicity
In man, no adverse effect has been reported on liver or kidney function, the 
hematopoietic system or on the blood vessels. The reported incidence of lactic acidosis 
in patients receiving metformin hydrochloride is very low (approximately
0.03 cases / 1000 patient/years with approximately 0.015 fatal cases / 1000 
patient/years). The consecutive administration of both phenformin and metformin to 
the same patient has allowed for the demonstration of a fundamental difference 
between these two biguanides in relation to lactacidemia. In some instances, patients 
developed hyperlactacidemia with phenformin when the same patients were 
presenting normal lactic acid levels while being treated with metformin. In other 
instances, hyperlactacidemia observed during a treatment with phenformin did regress 
when metformin was substituted for phenformin. Metformin may increase 
lactacidemia but to a degree that is clinically less significant than the elevation seen 
after phenformin.
Teratology
Teratological studies were carried out in albino rats divided in three groups: No 
abnormalities were found, even when high doses were administered. The number of 
animals was the same in each group. Death rate in the three groups of treated animals 
and controls was approximately the same. However, the number of living animals in 
each group treated was slightly lower than in the control group. Also, the frequency 
of litters exceeding 10 live animals was slightly higher in the control group. A loss of 
weight at the time of weaning has been observed when compared to the control 
group. Nevertheless, on a statistical basis, differences were shown to be non- 
significant. There is no difference between the groups of treated animals and the 
control group regarding the number of stillborn. The number of deaths after birth was 
slightly higher in metformin treated groups than in the control group, but the 

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comparison of average death rates is not significant (p > 0.05).
9.1.6 How Supplied: It will not be provided by the study (Commercial supply)
9.1.7 Storage: Store at room temperature (15° to 30°C) in well-closed containers
9.1.8 Dose Specifics: 1000 mg twice daily orally, continuously to the end of study 
(for details of dose escalation please see Section 5.4.3). The tablets should be taken at 
approximately the same time every day.
9.1.9 Route of Administration: Metformin is administered orally, with food
9.1.10 Side Effects: Please refer to protocol section heading “Clinical Experience 
with Metformin” for a summary of adverse effects.
9.1.11 Dose Adjustments
Please see section 5.5.1.
9.1.12 Concomitant Therapy 
Permitted
Subjects may receive bisphosphonates, at the discretion of their treating physician, 
before during or after randomization and study treatment with metformin.
Not permitted
Sulfonylureas, thiazolidenediones or insulin for any reason unless these drugs become 
necessary to treat a new diagnosis of diabetes mellitus while on study therapy in 
which case the patient will discontinue study treatment. Subjects should avoid 
excessive alcohol intake (i.e. less than 3 alcoholic beverages on any given day). 
Androgen deprivation therapy is not permitted.
9.2Bicalutamide (Please refer to the package insert for more comprehensive 
information.)
9.2.1 Availiability: Bicalutamide is commercially available
9.2.2 Other Names: Casodex®, a commercially available agent.
9.2.3 Chemical  Name:  Propanamide,  N-[4-cyano-3-(trifluromethyl)phenyl]-3-[4- 
fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+/-)
9.2.4 Molecular Formula: C18H14N2O4F4S
9.2.5 Mode  of  Action:  Competitive  inhibitor  of  androgen  binding  to  cytosolic 
androgen receptors.

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9.2.6 How  Supplied:  White,  film-covered  oral  tablet  containing  50  mg  of 
bicalutamide. It will not be provided by the study (Commercial supply)
9.2.7 Storage: Controlled room temperature, 20-25°C.
9.2.8 Dose Specifics: 50 mg/daily orally beginning Cycle 3 (week 13), continuously 
to the end of study (please see Section XXX). The tablet should be taken at 
approximately the same time every day.
9.2.9 Route of Administration: Oral, may be taken with or without food.
9.2.10 Side Effects:
The most serious side effect that has been associated with bicalutamide is severe liver 
injury, which has been reported in approximately 1% of patients in controlled clinical 
trials. Hepatotoxicity typically occurs within the first three to four months of continuous 
treatment. It is not known whether the regimen used in this trial can cause liver injury. 
Transaminase levels will be drawn every 4 weeks. Other common side- effects of 
bicalutamide overlap those of leuprolide acetate, including hot flashes, generalized 
pain, asthenia, constipation, diarrhea, nocturia, testicular atrophy, and gynecomastia.
10.0  ADVERSE EVENTS
10.1
Definition of Adverse Experience
10.1.1 Adverse Events (AE) is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the 
use of a medicinal (investigational) product, treatment or procedure regardless of 
whether it is considered related to the medical treatment or procedure (NCI CTEP 
Guidelines March 28, 2011).
10.1.2 Serious Adverse Event (SAE) is an AE that is fatal or life threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization (for > 
24 hours), persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or is a congenital anomaly/ birth defect,  
or results in any important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered an SAE when, based 
upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the above outcomes. A “life- 
threatening” adverse event places the patient at immediate risk of death in the 
judgment of the investigator or sponsor.
10.1.3 Severity Rating
The investigator will evaluate the severity of each adverse event. NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity 

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tables provided in the protocol define severity. If not included in CTCAE      
v.4.0, severity is expressed in numerical grade using the following definitions:
1.
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2.
Grade 2: Moderate-minimal, local or noninvasive intervention indicated; 
limiting age appropriate instrumental ADL.
3.
Grade 3: Severe-severe or medically significant but not immediately life- 
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self care ADL.
4.
Grade 4: Life-threatening consequences; urgent intervention indicated.
5.
Grade 5: Death related to AE
10.1.4 Attribution/Relationship to study drug

Definite – clearly related

Probable – likely related

Possible – may be related

Unlikely – doubtfully related

Unrelated – clearly not related
10.1.5 Expectedness
An Expected Adverse Event is one where the specificity or severity is consistent 
with the current information available from the resources.
An Unexpected Adverse Event is one where the nature, severity, or frequency of 
the event is related to participation in the research is not consistent with either:
1. The known or foreseeable risk of adverse events associated with the 
procedures involved in the research that are described in (a) the protocol-related 
documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document, 
and (b) other relevant sources of information, such as product labeling and 
package inserts: or
2. The expected natural progression of any underlying disease, disorder, or 
condition of the subject (s) experiencing the adverse event and the subjects(s) 
predisposing risk factor profile for the adverse event.
(OHRP Guidance on reviewing unanticipated problems 2007)
10.2 Recording and Reporting Responsibilities
10.2.1 Investigative site recording responsibilities:
1.
Upon identification of an AE or SAE, the site investigator will utilize the 
above definitions to properly classify the event. Each category listed above must 
be recorded for each event.
2.
All AEs and SAEs will be recorded in the “AE case report forms” (CRF) 

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and in progress reports with details about the grade and attribution of each 
episode, action taken with respect to the study drug, and the patient’s outcome 
will be recorded in the CRF. All events will be recorded on case report forms for 
the duration of the study until they resolve.
3.
All reportable SAEs will be recorded on the FDA MedWatch form 3500a. 
After submitting the initial report it may be necessary to submit follow up reports 
to the Sponsor should the event require further investigation.
10.2.2 Investigative site reporting responsibilities:
1. The investigator/ site is responsible to report all SAEs which occur on or after 
the first day of treatment to the sponsor within 24 hours of becoming aware of the 
event. All subsequent SAEs must be reported for up to 30 days after the last 
treatment.
2.
Each investigator is responsible to report all AEs/SAEs to their local IRB 
following guidelines set by that IRB. The FCCC OCR reserves the right to 
request an event be reported to the IRB at their discretion. Copies of events 
reviewed by the IRB must be sent by email to SAE.FCCC@fccc.edu. 
3.
If the investigator or IRB feels the event warrants a revision to the informed 
consent that was not already initiated by the OCR, draft revisions will be made in 
track changes and submitted to the OCR for consideration. Any consent revisions 
must receive OCR approval prior to submission to the IRB.
4.
Any investigator who is in doubt of whether a particular AE needs to be 
reported is directed to call the Study Monitor for confirmation with the Sponsor- 
Investigator.
5.
If the results of an investigator or OCR investigation show an adverse event 
not initially determined to be reportable is so reportable, the investigator will 
report the event following the above guidelines based on the date the 
determination is made.
6.
Copies of all related correspondence and reporting documents must be 
submitted to the ISRU and will be maintained in the trial master file.
The participating site should report events to: 
Investigator-Sponsored Research Unit
Office of Clinical Research
Fox Chase Cancer Center 
SAE.FCCC@fccc.edu 
10.2.3 Sponsor Reporting Responsibilities:
1.
Adverse events which meet all of the following criteria must be reported to 
all participating institutions for IRB submission within 2 weeks of notification of 
the event.
i.
Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related documents, 

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such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the subject population being 
studied;
ii.
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); and
iii.
Serious (refer to above definition) or otherwise one that suggests that the 
research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized.
2.
If the adverse event requires modification of the study protocol and 
informed consent, these changes will be provided to all participating institutions 
in the form of an amendment from the OCR for each site’s IRB of record along 
with the report of the adverse event.
3.
Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at OCR.
4.
SAEs that are related, unexpected, fatal, or life-threatening are reportable 
through the Food and Drug Administration (FDA) MedWatch program by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information. Further information on the timing of submissions are as directed by 
FDA guidelines (http://www.fda.gov/medwatch/index.html). Serious, 
unexpected events that suggest significant clinical risk will be submitted to within 
15 calendar days after initial receipt of this information.
Food and Drug Administration: 
Telephone 1-800-FDA-1088 
Fax 1-800-FDA-0178
http://www.fda.gov/medwatch/report.htm
Mandatory Drug Reporting: 
Central Document Room
Center for Drug Evaluation and Research 
Food and Drug Administration
12229 Wilkins Avenue
Rockville, MD 20852
Office of Post-Marketing Drug Risk Assessment (HFD 730) 
Center for Drug Evaluation and Research
Food and Drug Administration 
5600 Fishers Lane
Rockville, MD 20857
(301) 827-3169 for any further questions regarding where to send drug 
mandatory reporting forms
11.0   STATISTICAL CONSIDERATIONS
11.1
Sample size

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We will test the hypothesis that only 20% of patients on either arm of the study will 
have undetectable PSA at 32 weeks, versus the alternative that 40% of arm B patients will. 
An initial cohort of 39 patients and, if continued, a second cohort of 27 patients will be 
randomized 2:1 to arms B and A respectively.
After stratification for prior therapy we will randomize, 2:1, nominally 13 patients to 
arm A and 26 patients to arm B. Because of post stratification randomization, the exact 
numbers in the two arms may vary slightly from 13 and 26, but the total patient number in 
the the initial cohort will be exactly 39 and the final sample number be exactly 66. Our intent 
is to compare the proportions of patients with undetectable PSA at 32 weeks. This is most 
simply described by the difference (E1/26) – (C1/13), where C1 and E1 are the numbers of 
undetectable PSAs in arms A and B respectively. The cut point for continuation of the trial 
past the first cohort requires that
(E1/26) – (C1/13) > -2/13 = -0.1538462…. To avoid confusion due to round off of such 
fractions, we identify the decision boundary by 13 E1 – 26 C1 > -52, exactly equivalent the 
first expression, and obtained by multiplying all terms by 13*26.
If 13 E1 – 26 C1 exceeds -52 AND E1 is at least 6 then we will randomize an 
additional 9 patients to arm A and 18 patients to arm B. Otherwise the study will be 
terminated and the null hypothesis accepted. Letting C2 and E2 be the numbers of 
undetectable PSAs in the second cohort, we will finally reject the null hypothesis if 22(E1 + 
E2) – 44(C1 + C2) is at least 88 and E1 + E2 is at least 14. The initial cohort will consist of 
39 and the final cohort of 27 patients for a total of 66 patients. If the true null is 20% 
undetectable PSAs type I error will be 3.24% and power will be 80.3%. In this case the 
chance of early stopping under the null will be 60% but will be 3.23% if the true arm B 
fraction of undetectable PSAs is 40%.
If the null (arm A) fraction undetectable PSAs is 25% type I error increases to 10.9% 
and power increases to 83.3% if the arm B fraction undetectable is 45% (20% higher). If the 
null fraction is 30% type I error increases to 19.7% and power to 83.2% (arm B 50%, 20% 
higher).
The above discussion is based on the exact 2:1 split in the combined strata. This may 
not occur so the table below describes the decision boundaries for all possible outcomes of 
the split. In all cases study power is at least 80% and type I error is less than 5%. Type I error 
when the null fraction is 30% is always under 20%. To use the table we compute nc1 E1 – 
ne1 C1 where nc1 and ne1 are the actual numbers of arm A and arm B respectively in the 
initial cohort of 39. If this number, nc1 E1 – ne1 C1 > -a1, and E1 > m1 in the table, then the 
trial may be continued past the initial cohort. Otherwise it is terminated and the null hypothesis 
accepted. If the second cohort is recruited, then nc2(E1+E2) – ne2(C1+C2) must be computed. 
nc2 and ne2 are the total numbers of patients in arms A and B respectively. If nc2(E1+E2) – 
ne2(C1+C2) is at least r and E1+E2 is at least m2 in the table, then the null hypothesis will 
be rejected. The table is indexed by nc1 and nc2 only. This is so because nc1+ne1 = 39 
invariably as does nc2+ne2 = 66. For example, suppose nc1 = 13 hence ne1 = 26. Then if E1 
= 7 and C1 = 4, E1 > m1 = 6 and 13 E1 – 26 C1 = 13 * 7 – 26 * 4 = 91 – 104
= -13, and -13 > -52, so the second cohort would be recruited. Finally, suppose nc2 = 22 
hence ne2 = 44 and suppose E2 = 9 and C2 = 2. Then E1+E2 = 9+7=16 > m2=14 and 
22(E1+E2) – 44(C1+C2) = 22*16 – 44*6 = 352-264 =88 which is at least r = 88. In this case 
the null hypothesis would be rejected.

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decision boundaries 
nc1 nc2
a1  m1
r
m2
12 21 -42
6
72
14
12 22 -42
6
88
14
12 23 -42
6
88
13
13 21 -52
6
72
14
13 22 -52
6
88
14 (this row used in example above)
13 23 -52
6
88
13
14 21 -68
6
72
14
14 22 -68
6
88
14
14 23 -68
6
88
13
11.2  Toxicity assessment
A DLT rate of 20% will be considered excessive for arm B. A rate of 5% is expected and 
acceptable. If 5 of the initial cohort in arm B experience DLT, the study will be halted for 
reassessment of dose. If 7 of arm B patients experience DLT the regimen will be 
considered too toxic. This set of rules has at least 80% chance of declaring arm B too toxic 
when the true DLT rate is 20%. This chance under the null is about 1%. The chance of 
halting the trial early is over 57% for a 20% DLT rate and less than 1% if this rate is only 
5%.
11.3 Secondary assessments
We will test the hypothesis that the fraction of arm A and arm B patients with at least 
85% reduction in PSA at 32 weeks will be the same. We will sort the 66 patients 32 week 
PSAs into groups above or below their grand median 32 week PSA.  We will then submit the 
doubly dichotomized data to Fisher’s exact test. The test will distinguish an odds ratio of
3.19 from one of 1.0 with 80% power and at most 10% type I error.
We will characterize the time to PSA progression and the time to onset of metastatic disease 
using the method of Kaplan and Meier. We will compare arms A and B for each of these end 
points with log-rank tests. Patients will be followed for PSA progression and for onset of 
metastatic disease for at least 60 months.
11.4
Definition of Populations for Analyses
All Treated Subjects: all subjects who are treated with bicalutamide (arm A) or 
bicalutamide and metformin (Arm B). All Randomized Subjects: all subjects who received 
treatment.
11.5
Safety Analyses
Safety analyses will be conducted on treated patients. All adverse events will be 
summarized 1) without regard to causal relationship and 2) by causal relationship to study 
drugs, based on the Investigator’s opinion. Worst toxicity grades per subject will be tabulated 
for selected adverse events and laboratory measurements. Any serious adverse event or 

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adverse event resulting in premature and permanent discontinuation of any study drug will be 
described in detail. Adverse events and other symptoms will be graded according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0
12.0  DATA SAFETY MONITORING PLAN
12.1 Monitoring Plan
FCCC ISRU will monitor the medical and study records of each participant accrued 
throughout the course of the study. In addition, the ISRU will collect and report data to the 
study Sponsor-Investigator who will review these data on a regular basis at a rate dependent on 
subject accrual. All serious adverse events (SAEs) will be reviewed on a real time basis first 
by the study site PI and subsequently by the ISRU and Sponsor-Investigator as applicable.
12.2 Data Safety Monitoring Board
Interim analysis of toxicity, outcome and ongoing scientific investigations will be 
performed at least every 6 months by the Fox Chase Cancer Center Data Safety Monitoring
Board (FCCC DSMB). In this capacity the FCCC DSMB will serve as an advisory committee 
to the Sponsor-Investigator. The FCCC DSMB will review those aspects of this trial that are 
outlined in the responsibilities section of the Data and Safety Monitoring Plan (DSMP). If 
the committee decides that changes should be made to this trial, it will make recommendations 
in writing to the Sponsor-Investigator, the Associate Director of Clinical Research, and the 
Protocol Management Executive Committee, which, in turn, have the authority to approve or 
disapprove these recommendations. These changes will be discussed with the Sponsor-
Investigator before they are implemented. These changes may include early termination of 
accrual. Other changes might include altering the accrual goals or changing the eligibility 
criteria for the trial.
13.0 Administrative
This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines.
13.1 Data Reporting
The FCCC Study Monitor will request case report forms to be completed within 2 weeks 
of the protocol visit. Participating sites are responsible to respond to queries prior to the next 
scheduled monitoring visit.
The ISRU is responsible for compiling and submitting data to the Sponsor-Investigator 
and statistician on an ongoing basis for monitoring as described in the data safety monitoring 
plan and reporting to the Data and Safety Monitoring Board.

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All patient information will be stored in an EDC system accessible only to the study 
team members for the purpose of entering, reviewing and analyzing data. Any paper records, 
such as case report files, produced will be stored in a secure location.
The ISRU is responsible for distributing and tracking review of all IND Action Letters, 
Safety Reports, study specific Serious Adverse Events.
13.2 Retention of Records
Time points for the retention of records are described in detail in the contract between 
the grantor and the OCR and passed on to the participating site. Please refer to the study 
specific terms for specific time points. In all cases the Study Monitor must be notified of any 
plans to move records to an offsite location prior to doing so.
13.3 Study Agents
Any study agent supplied through the OCR from the manufacturer or a third party 
distributor may not be used for any purpose outside the scope of this protocol. The agent 
may not be transferred to any party not participating in the clinical trial.
13.4 Informed Consent
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study. The 
case history for each patient shall document that informed consent was obtained prior to 
participation in the study. A copy of the informed consent documents must be provided to 
the patient or the patient’s legally authorized representative. If applicable, they will be 
provided in a certified translation of the local language.
Original signed consent forms must be filed in each patient’s study file or medical 
record with a copy in the study file.

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Lepone LM, Donahue RN, Grenga I, Metenou S, Richards J, Heery CR, Gulley JL, Schlom J. 
 Analysis of 123 peripheral human immune cell subsets: defining differences with age and between healthy 
donors and cancer patients not detected in analysis of standard immune cell types. J Circ Biomark. 2016; 5:5 
I doi: 10.5772/62322.

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APPENDIX I
Diary for
dosing.
(Name of Study Drug)
Study Participant’s Initials
Sequence #
Cycle # 
Instructions
Please complete this diary when taking your
.  Your prescribed dose is
.
 
should be taken orally
day for
days. You should take your dose at 
approximately the same time every day.
 
should be taken with / without (choose one or edit) food.
If you miss a dose, record this in your diary. Doses should not be doubled to make up for missed doses. 
If you vomit after taking a dose, record this in your diary. Do not take an additional dose to make up for 
this dose.
Bring your empty container or unused pills back to the hospital at the end of each cycle of treatment. 
There are certain medications that are prohibited while you are on this study. Please let your physician 
or protocol nurse know about all medications you are taking, and check with them before beginning any 
new medications.
If you have any questions, please contact your protocol coordinator
at
 
.

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Copyright© 2015 Fox Chase Cancer Center® Office of Clinical Research. All rights reserved.
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Study Participant’s Initials
Sequence #
Cycle # 
Study Drug Name 
Day
Date
Time
Dose
Reason, if dose not taken
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19

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20
21
22
23
24
25
26
27
28
Date
Study Participant Signature 
Study Participant’s Initials
Sequence #
Cycle # 
SECTION TO BE COMPLETED BY CLINICAL RESEARCH COORDINATOR
Total # of pills dispensed
Date  
 
Total # of pills returned
Date 
 
CRC Signature
Date 

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Copyright© 2015 Fox Chase Cancer Center® Office of Clinical Research. All rights reserved.
Version Date 01/24/2017
APPENDIX II
Below is a list of statements that other people with your illness have said are important. Please circle 
or mark one number per line to indicate your response as it applies to the past 7 days
Not
PHYSICAL WELL-BEING
at all
A little 
bit
Some- 
what
Quite 
a bit
Very 
much
GP1
I have a lack of energy ........................................................
0
1
2
3
4
GP2
I have nausea.......................................................................
0
1
2
3
4
GP3
Because of my physical condition, I have trouble
meeting the needs of my family ..........................................
0
1
2
3
4
GP4
I have pain...........................................................................
0
1
2
3
4
GP5
I am bothered by side effects of treatment ..........................
0
1
2
3
4
GP6
I feel ill ................................................................................
0
1
2
3
4
GP7
I am forced to spend time in bed.........................................
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not
at all
A little 
bit
Some- 
what
Quite 
a bit
Very 
much
GS1
I feel close to my friends.....................................................
0
1
2
3
4
GS2
I get emotional support from my family .............................
0
1
2
3
4
GS3
I get support from my friends .............................................
0
1
2
3
4
GS4
My family has accepted my illness .....................................
0
1
2
3
4
GS5
I am satisfied with family communication about my
illness ..................................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person who is my main
support) ...............................................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it,
please mark this box
and go to the next section.

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GS7
I am satisfied with my sex life ............................................
0
1
2
3
4
Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days.
EMOTIONAL WELL-BEING
Not
at all
A little 
bit
Some- 
what
Quite 
a bit
Very 
much
GE1
I feel sad ..............................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with my illness..........
0
1
2
3
4
GE3
I am losing hope in the fight against my illness..................
0
1
2
3
4
GE4
I feel nervous.......................................................................
0
1
2
3
4
GE5
I worry about dying.............................................................
0
1
2
3
4
GE6
I worry that my condition will get worse ............................
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not
at all
A little 
bit
Some- 
what
Quite 
a bit
Very 
much
GF1
I am able to work (include work at home) ..........................
0
1
2
3
4
GF2
My work (include work at home) is fulfilling.....................
0
1
2
3
4
GF3
I am able to enjoy life .........................................................
0
1
2
3
4
GF4
I have accepted my illness ..................................................
0
1
2
3
4
GF5
I am sleeping well ...............................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for fun ......................
0
1
2
3
4
GF7
I am content with the quality of my life right now .............
0
1
2
3
4

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Copyright© 2015 Fox Chase Cancer Center® Office of Clinical Research. All rights reserved.
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Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days.
ADDITIONAL CONCERNS
Not at
all
A little 
bit
Some- 
what
Quite 
a bit
Very 
much
C2
I am losing weight ...............................................................
0
1
2
3
4
C6
I have a good appetite..........................................................
0
1
2
3
4
P1
I have aches and pains that bother me .................................
0
1
2
3
4
P2
I have certain parts of my body where I experience pain....
0
1
2
3
4
P3
My pain keeps me from doing things I want to do..............
0
1
2
3
4
P4
I am satisfied with my present comfort level ......................
0
1
2
3
4
P5
I am able to feel like a man .................................................
0
1
2
3
4
P6
I have trouble moving my bowels .......................................
0
1
2
3
4
P7
I have difficulty urinating....................................................
0
1
2
3
4
BL2
I urinate more frequently than usual....................................
0
1
2
3
4
P8
My problems with urinating limit my activities ..................
0
1
2
3
4
BL5
I am able to have and maintain an erection .........................
0
1
2
3
4
Patient Name   
Signature
 
Date
 

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Copyright© 2015 Fox Chase Cancer Center® Office of Clinical Research. All rights reserved.
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