a phase ib/ii study of
7.2 cyclophosphamide (cytoxan)

Product description: Lyophilized CYTOXAN® (cyclophosphamide for injection, USP) is a sterile white lyophilized cake, or partially broken cake, containing 75 mg mannitol per 100 mg cyclophosphamide (anhydrous). Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. Cyclophosphamide is a white crystalline powder with the molecular formula C7H15Cl2N2O2P•H2O and a molecular weight of 279.1. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate.  
Cyclophosphamide is soluble in water, saline, or ethanol and has the following structural formula.  
Please refer to the package insert for complete product details.
a phase ib/ii study of
classification alkylating agent

Mode of Action: Cyclophosphamide is biotransformed principally in the liver to active alkylating metabolites by a mixed function microsomal oxidase system. These metabolites interfere with the growth of susceptible rapidly proliferating malignant cells. The mechanism of action is thought to involve cross-linking of tumor cell DNA. Metabolism: Cyclophosphamide is well absorbed after oral administration with a bioavailability greater than 75%. The unchanged drug has an elimination half-life of 3 to 12 hours. It is eliminated primarily in the form of metabolites, but from 5 to 25% of the dose is excreted in urine as unchanged drug. Several cytotoxic and noncytotoxic metabolites have been identified in urine and in plasma.  
Concentrations of metabolites reach a maximum in plasma 2 to 3 hours after an intravenous dose.  
Storage and Stability: Storage at or below 77°F (25°C) is recommended; this product will withstand brief exposure to temperatures up to 86°F (30°C) but should be protected from temperatures above 86°F (30°C).  
Reconstituted Lyophilized CYTOXAN are chemically and physically stable for 24 hours at room temperature or for six days in the refrigerator; it does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.  
Preparation: Refer to the package insert for standard preparation instruction. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Lyophilized CYTOXAN should be prepared for parenteral use by adding Sterile Water for Injection, USP, to the vial and shaking to dissolve. Use the quantity of diluent shown in the package insert.  
Administration: Route of administration: Cyclophosphamide will be administered as an IV infusion over 60-120 minutes. Solutions of Lyophilized CYTOXAN will be infused intravenously in the following: Dextrose Injection, USP (5% dextrose); Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sodium chloride); 5% Dextrose and Ringer's Injection; Lactated Ringer's Injection, USP; Sodium Chloride Injection, USP (0.45% sodium chloride); Sodium Lactate Injection, USP (1/6 molar sodium lactate). Patient care implications: To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing CYTOXAN sterile powder for injection. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.  
Incompatibilities/Contraindications: Continued use of cyclophosphamide is contraindicated in patients with severely depressed bone marrow function. Cyclophosphamide is contraindicated in patients who have demonstrated a previous hypersensitivity to it.  
| Myelosuppression Liver function test abnormalities Impairment of fertility Rash  Skin pigmentation changes Nail changes Stevens-Johnson syndrome Congestive heart failure Infusion-related symptoms such as fever, chills,  rigors, headache Abdominal discomfort Nausea Vomiting Diarrhea Mucositis, oral ulceration Alopecia Anorexia   | Pain Hemorrhagic cystitis  Hemorrhagic ureteritis  Urinary bladder fibrosis Renal tubular necrosis  Hemorrhagic colitis Intersitital pnemonitis Intersitital pulmonary fibrosis Jaundice Infections Secondary malignancy Anemia, thrombocytopenia, leukopenia,  neutropenia Anaphylaxis SIADH Malaise Asthenia   |
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a phase ib/ii study of
side effects

Availability: CYTOXAN® (cyclophosphamide for injection, USP) contains cyclophosphamide monohydrate and is supplied in vials for single-dose use.  
Accountability: Drug accountability records will be maintained by the investigational pharmacy as per standard pharmacy practice.
a phase ib/ii study of
8.0 correlative/special studies 8.1 pharmacokinetic

Whole blood for pharmacokinetic assessments of eribulin and cyclophosphamide will be drawn in 6 mL tubes on Cycle 1 Day 1 pre-dose, at the end of eribulin infusion, and at 15 min, 30 min, hour 1, 2, 3, 4, 6 and 8 after the end of eribulin. Participation in the pharmacokinetic assessment portion of the protocol, i.e. recruitment during dose-escalation will be limited to patients enrolled in the Phase Ib portion of the trial. Description of collection, handling and shipping procedures of PK samples will be provided in Appendix F.  
Handling of Specimens(s) - Standard phlebotomy handling Site(s) Performing Correlative Study - XenoBiotic Laboratories, Inc.  
Shipping of Specimen(s) –  
  
Blood will be processed and shipped on dry ice by overnight mail on Monday-Wednesday to: Notification on the day of shipping should be sent to:
a phase ib/ii study of
8.2 circulating tumor cells

Collection of Specimen(s) Three tubes of blood will be collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment (2 CellSave tubes and 1 purple top tube) in each patient. 7.5 mL of blood is required per CellSave tube, it is critical that the tube be completely filled. 10mL is required in each purple top tube. One CellSave tube will be used for CTC enumeration, the second CellSave tube will be used for sorting and WGA with CGH/sequencing. The purple top tube will be used for gene expression if there is adequate sample. If the first sample has ≥ 5 CTC/mL, on Cycle 2 Day 1, 1 CellSave and 1 purple top tube will be collected for CTC enumeration and aCGH/gene expression.  
2 CellSave tubes and 1 purple top tube should be obtained at end of study if at all possible.  
Handling of Specimens(s) - Standard phlebotomy handling Site(s) Performing Correlative Study - John Park MD laboratory, UCSF Shipping of Specimen(s) - UCSF: No shipment is required. Samples will be hand-delivered at room temperature to the Park laboratory immediately after they are obtained and processed immediately.  
Outside sites: Blood will be shipped at room temperature by overnight mail to:
Notification on the day of shipping should be sent to:
Special instructions will be provided for Friday shipping.  
8.3 Pharmacogenomic (PG studies)
One 7.5 mL purple top tube will be collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment. DNA extraction and analysis for three novel candidate genes which may relate to development of peripheral neuropathy, FZD3, FGD4 and EPHA5 will be performed.  
Other exploratory analysis may also be performed. If adequate sample remains, a genome scan at UCSF may also be performed.  
Handling of Specimens(s) - Standard phlebotomy handling Site(s) Performing Correlative Study - Deanna Kroetz laboratory, UCSF
Shipping of Specimen(s) –
UCSF: No shipment is required. Samples will be sent by courierat room temperature to the Kroetz laboratory immediately after they are obtained and processed immediately.  
Outside sites: Blood will be shipped at room temperature by overnight mail to:
a phase ib/ii study of
8.4 archived tissue analysis

Collection of Specimen(s) FFPE (formalin-fixed paraffin embedded) archived tumor blocks from prior surgery or biopsies with corresponding H&E slides, will be requested for all patients, although they are not required and should not delay enrollment. If necessary, the research team will contact outside institutions to obtain specimens.  
All patients consenting to this protocol will be presented with a Tumor Specimen Release Form.  
These specimens will become the property of UCSF Cancer Center and will be stored at the Cancer Center Tissue Core at UCSF . Mutational analyses will be performed on tumor tissue and correlated with results from CTC studies described above.
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9.0 study procedures 9.1 screening

Screening radiographic studies, EKG, and laboratory studies must be performed within 30 days of starting protocol therapy.  
If laboratory studies are performed within 14 days of starting protocol therapy, these can serve as day one values.  
CT scan of chest/abdomen/pelvis Bone scan for patients with known or suspected bone metastases PET/CT scan with a diagnostic CT may be substituted for the above two scans Additional radiographic studies for known sites of disease not evaluated by the above scans EKG CBC with differential Serum biochemical panel including Na, K, HC03-, Cl-, Ca, Mg, Phos, BUN, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase Negative serum pregnancy test for females of child-bearing potential Concomitant medication review
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9.2 assessments and procedures during

Once the patient is confirmed to be eligible based on screening assessments, the following study assessments will be performed (see also study calendar below). Each cycle will be 21 days (3 weeks). Patients will receive eribulin on day 1 and 8 and cyclophosphamide on day 1 of each cycle. Treatment delay of greater than 7 days or missing >1 out of the 2 weekly doses in the first cycle due to toxicity will be considered a DLT. If a dose is held a week, then that week's dose is omitted and treatment resumes at the next scheduled infusion without prolongation of the 3 week cycle.
a phase ib/ii study of
cycle 1 (day 1)

The following assessments will be performed prior to receiving treatment on Cycle 1 Day 1:
Medical history, physical examination including vital signs, ECOG performance status Adverse event and con-med review CBC with differential, serum biochemical panel (labs performed for screening within 14 days of treatment start can be used for baseline values)
EKG - to be read by a cardiologist Pharmacokinetic blood work - day 1 only Research blood work - at baseline and per schema EORTC QLQ-C30 10-point Modified Total Neuropathy Score (mTNS) FACT/GOG-Ntx Cycle 1 Day 8 CBC with differential, serum biochemical panel EKG - to be read by clinician. If there is an unanticipated abnormal EKG, a cardiologist will be consulted prior to patient treatment
a phase ib/ii study of
cycle 2 and every cycle

The following assessments will be performed on day 1 and day 8 (or within 24 hours prior) of every cycle:
CBC with differential, serum biochemical panel For Phase 2, Day 8 visits will only occur in Cycle 2.  
The following assessments will be performed on day 1 of (or within 72 hours prior to) every cycle:
Medical history and physical exam Adverse event and con-med review 10-point Modified Total Neuropathy Score (mTNS) FACT/GOG-Ntx
a phase ib/ii study of
imaging

Phase 1b (all solid malignancies) At 6 weeks after study start, then every 6 weeks until end of study therapy CT scan of chest/abdomen/pelvis Bone scan should be performed as indicated to evaluate change in symptoms PET/CT with diagnostic CT scan can substitute for the two above studies Additional radiographic studies for known sites of disease not evaluated by the above scans Pertinent tumor markers per treating physician's discretion
a phase ib/ii study of
phase ii (breast cancer only)

At 6 weeks after study start, then every 9 weeks until end of study therapy CT scan of chest/abdomen/pelvis Bone scan should be performed as indicated to evaluate change in symptoms PET/CT with diagnostic CT scan can substitute for the two above studies Additional radiographic studies for known sites of disease not evaluated by the above scans Pertinent tumor markers per treating physician's discretion EORTC QLQ-C30 6 weeks, 3 months, 12 months, 18 months, 24 months, and/or at study termination.
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9.3 study termination

The following assessments will be performed when the patient goes off-study:
Physical exam Adverse event and con-med review CBC with differential, serum biochemical panel EORTC QLQ-C30 10-point Modified Total Neuropathy Score (mTNS)
FACT/GOG-Ntx Radiographic imaging of evaluable and measurable disease
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9.4 follow-up

Patients' clinical data will be collected monthly for the first 3 months after completion of the clinical trial, then every 6 months. These biennial assessments will continue until death or for duration of up to at least ten years. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event and then for at least ten years to obtain recurrence/survival data.  
| Table 9-1 Study Calendar                                        | Cycle 3 and                                     |                    |            |     |     |     |     |    |
|-----------------------------------------------------------------|-------------------------------------------------|--------------------|------------|-----|-----|-----|-----|----|
| Cycle 1                                                         |                                                 |                    |            |     |     |     |     |    |
| (Days 1-21)                                                     | Cycle 2                                         | subsequent  cycles | Off  study |     |     |     |     |    |
| Test/Study                                                      | Prestudy                                                 | D1                 | D8         | D12 | D8  | D12 | D8  |    |
| Medical History                                                 | X1                                              | X                  | X2         | X2  | X   |     |     |    |
| Physical Exam3                                                  | X1                                              | X                  | X2         | X2  | X   |     |     |    |
| Informed consent                                                | X1                                              |                    |            |     |     |     |     |    |
| Inclusion/exclusion                                             | X1                                              |                    |            |     |     |     |     |    |
| Toxicity assessment (including weight)                          | X                                               | X                  | X          | X   | X18 | X   |     |    |
| PK4                                                             | X                                               |                    |            |     |     |     |     |    |
| PG5                                                             | X                                               |                    |            |     |     |     |     |    |
| EKG6                                                            | X1                                              | X                  |            |     |     |     |     |    |
| CBC, Diff.7                                                     | X1                                              | X1                 | X          | X   | X   | X   | X18 | X  |
| Chemistry8                                                      | X1                                              | X1                 | X          | X   | X   | X   | X18 | X  |
| CTC enumeration and  analysis9                                  | X                                               | X                  | X          |     |     |     |     |    |
| Genome scan10                                                   | X                                               |                    |            |     |     |     |     |    |
| Archival tumor tissue  collection11                             | X                                               |                    |            |     |     |     |     |    |
| Eribulin administration12                                       | X                                               | X                  | X          | X   | X   | X   |     |    |
| Cyclophosphamide  administration                                | X                                               | X                  | X          |     |     |     |     |    |
| Pregnancy Test13                                                | X1                                              |                    |            |     |     |     |     |    |
| Staging Studies  (RECIST)14                                     | X                                               | X                  | X          |     |     |     |     |    |
| EORTC QOL-C30  questionnaire15                                  | X                                               | X                  | X          |     |     |     |     |    |
| Neuropathy  assessment16                                        | X                                               | X                  | X          | X   |     |     |     |    |
| FACT-GOG Ntx17                                                  | X                                               | X                  | X          | X   |     |     |     |    |
| Evaluations should continue as noted for all subsequent cycles. | Day 1 visit procedures for any cycle of therapy |                    |            |     |     |     |     |    |  
Evaluations should continue as noted for all subsequent cycles. Day 1 visit procedures for any cycle of therapy are allowed a window of ± 3 days unless otherwise noted.  
X1 Pre-study tests may be used for Day 1 tests if within 2 weeks and no significant changes have occurred.  
X2 D1 physical exam and history in subsequent cycles may be done within 72 hours prior to next cycle. X3 Physical Exam includes ECOG status, vital signs, height and weight.
X4 Pharmacokinetic samples to be collected from patient at study site Day 1 pre-dose, at the end of eribulin infusion, and at 15 min, 30 min, 1, 2, 3, 4, 6 and 8 hours after the end of eribulin in phase Ib and analyzed by an outside vendor.  
X5 Pharmacogenomic samples to be collected from patient at study site will be collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment and analyzed by Dr. Deanna Kroetz' laboratory at UCSF.  
X6 EKG will be performed at baseline and analyzed by a cardiologist. EKG performed on cycle 1 day 8 will be analyzed by the clinician. If there is an unanticipated abnormal EKG, a cardiologist will be consulted prior to patient treatment.  
X7 Hemoglobin, hematocrit, platelets, total white blood cell count (WBC) and differential.  
X8 BUN, creatinine, sodium, potassium, chloride, CO2 (HCO3), glucose, calcium, albumin, total protein, total bilirubin, alkaline phosphatase, LDH (melanoma only), AST/SGOT, ALT/SGPT, phosphorous, magnesium. If total bilirubin is greater than the upper limit of normal, direct and indirect bilirubin should be performed. Biochemistry tests should be obtained after patient has fasted, if possible.  
X9 CTC (circulating tumor cells) will be collected using whole blood by study site and enumerated by Dr. John Park's lab at UCSF using either CellSearch or IE/FACS. The first sample will be collected on cycle 1 day 1 collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment. Baseline/cycle 1 analysis will include genomic profiling and gene expression for tubulin mutations and others. If initial sample shows CTC ≥ 5/mL, a second sample with be enumerated and aCGH/gene expression may be performed on cycle 2 day 1.  
X10 Genome scan to be collected by study site, processed by the DNA bank at UCSF and then analyzed at Dr. Kwok's laboratory at UCSF.  
X11 If available, archival tumor tissue will be collected from the pathology department and analyzed for expression profiling including tubulin mutations and proteomics.  
X12 Treatment delays due to patient coordination are allowed for the following: Cycle 1, Day 8 (eribulin delay up to 1 day), Cycle 2+, Day 1 (treatment delay up to 14 days), and Cycle 2+, Day 8 (delay treatment up to 3 days). Note - treatment or visit delays due to public holidays, weather conditions, or natural disasters, do not constitute protocol violations.  
X13 Pregnancy test is for women of child bearing potential and will be assessed by serum hcg.  
X14 Baseline evaluations should be performed not more than 30 days prior to the beginning of the treatment.  
Scans should be performed as detailed in section 9.2 every 6 weeks (2 cycles) for phase Ib, and at 6 weeks, then every 9 weeks for phase II until disease progression or end of study therapy for any reason. A 7 day variation in timing before or after the scheduled scan date is allowed to facilitate scheduling.If patients remain on study for more than one year from study start, these assessments will be optional.  
X15 EORTC QLQ-C30 questionnaire will be performed at baseline (within 7 days of cycle 1 day) and thereafter at 6 weeks, 3 months, 12 months, 18 months, 24 months, and/or at study termination. Questionnaires will be completed prior to drug administration.  
X16 Neuropathy will be assessed using the 10-point Modified Total Neuropathy Score (mTNS) at the start of each cycle and at study termination.  
X17 Patient assessment of neuropathy will be assessed using the FACT-GOG-Ntx 11 point questionnaire at the start of each cycle and at study termination.  
X18 Cycle 3+, Day 8 visits are only required for Phase 1. For Phase 2, toxicity assessment will only be done on Day 1 of cycles 3 and beyond.
a phase ib/ii study of
10.0 criteria for evaluation 10.1

For the purposes of this study, patients should be re-evaluated for response at 6 weeks (after 2 cycles), then every 6 weeks (phase Ib) or 9 weeks (phase II) until end of study therapy. A one week window in scans is allowable to facilitate scheduling of scans; however every effort should be made to keep the scans on schedule. Confirmatory scans will not be performed since this is a Phase I/II trial and the primary endpoints are safety, toxicity, and clinical benefit rate. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) (Eisenhauer, Therasse et al. 2009). Changes in the largest diameter (uni-dimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria.  
10.1.1 Response Definitions Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first study treatment. Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease.  
The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
a phase ib/ii study of
10.1.2 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter for non-nodal lesions and short axis for nodal lesions to be recorded) as >20 mm by chest x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).  
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed.  
Non-measurable disease: All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered nonmeasurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable.  
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts.  
'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.  
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for nonnodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.  
Non-target lesions: All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.  
10.1.3 Methods for evaluation of measurable disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally.  
As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 1.1 guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible.  
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST 1.1 measurements. If the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 1.1 measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not
a phase ib/ii study of
advised.

Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published (Bubley, Carducci et al. 1999; Rustin, Quinn et al. 2004; Scher, Halabi et al. 2008). In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer (Vergote, Rustin et al. 2000). Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain).  
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment)
and progressive disease.  
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible new sites of disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at followup is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. Both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
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evaluation of target lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).  
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response.  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.  
Note: Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the Principal Investigator.
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evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Table 10-2. Evaluation of Patients with Measurable Disease (i.e., Target Disease) Target  Non-Target  New  Overall  Best Overall Response  Lesions Lesions Lesions Response when Confirmation is  Required* CR CR No CR >4 wks. Confirmation** CR NonCR/Non-PD No PR >4 wks. Confirmation** CR Not  No PR evaluated PR NonCR/NonPD/not  evaluated No PR SD NonCR/NonPD/not  evaluated No SD documented at least once  >4 wks. from baseline** PD Any Yes or  PD No no prior SD, PR or CR Any PD*** Yes or  PD No Any Any Yes PD * See RECIST 1.1 manuscript for further details on evidence of a new  lesion. ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non-target  lesions may be accepted as disease progression.   |
|---|  
Note: Patients with a global deterioration of health status requiring  
 discontinuation of treatment without objective evidence of disease progression at that time should be reported as "symptomatic deterioration." Every effort should be made to document the objective progression even after discontinuation of treatment.  
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since  SD is increasingly used as an endpoint for assessment of efficacy in some trials so  to assign this category when no lesions can be measured is not advised |               |                    |  
10.1.5 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.  
Response Review: N/A
a phase ib/ii study of
11.0 statistical considerations 11.1 study

The study will follow a standard dose-confirmation schema (phase Ib portion) with 3 to 6 patients per cohort (3+3 design) for a total of 9-18 patients. The starting dose level will consist of eribulin mesylate 1.1 mg/ m2 on days 1 and 8 followed by cyclophosphamide 600 mg/ m2 on day 1 of a 21-day cycle.  
Enrollment to successive cohorts up to dose level +1 will be performed according to the table shown below, to establish the MTD. If 2 or more dose-limiting toxicities (DLTs) are observed at level 0, one dose reduction (to level -1) is built in to the study design. All patients at a given dose level will be followed on treatment for at least 3 weeks before accrual to the next cohort can commence. There will be no intra-patient dose escalation allowed. For any dose cohort, if a patient is removed from study for reasons that are clearly not treatment-related, then an additional patient will be accrued to that dose level. For the purposes of Phase I dose escalation, DLTs will be defined as any treatmentrelated toxicity occurring within the first 21 days of combination therapy as grade 3 or 4 clinically evident non-hematologic toxicity; grade 4 neutropenia or thrombocytopenia lasting > 7 days or febrile neutropenia; or any clinically significant toxicity grade 2 or higher that requires more than 14 days to resolve. The dose-expansion (phase II portion) will enroll 40 patients to detect a clinically meaningful benefit rate (efficacy and response including complete response, partial response and stable disease) of at least 25% in the study cohort. Using a two-stage Simon's minimax design, the null and alternative hypothesis will be H0: p0 < 10% versus Ha: p1 > 25% for proportion of patients with complete or partial response or stable disease by RECIST criteria. Based on defined p0=10% and p1=25% under the type I error of 5% and the type II error rate of 20%, the sample size for the first stage will be 22 patients. If 2 or fewer responses are observed in the first 22 patients (after all patients in the first stage have completed at least 2 months of treatment), the study will be terminated in the first stage; otherwise, the study will be expanded by additional 18 patients. If there are 7 or fewer responses are observed by the end of the second stage, no further investigation of the drug is warranted. If the clinical benefit rate is less than 10%, the probability of ending the study during the first stage is 62%. If the clinical benefit rate is greater than 25%, the probability that the study will be stopped in the first stage is 6%.  
The circulating tumor cell data, pharmacodynamic and pharmacogenomic exploratory analysis will be reported using descriptive statistics only.
a phase ib/ii study of
11.2 accrual objectives

Maximum of 18 patients in phase Ib, 40 in phase II.
a phase ib/ii study of
11.2.1 replacement of patients

For dose escalation decisions in Cycle 1, each cohort must have at least 3 patients evaluable for toxicity (unless the first 2 patients in the cohort experience a DLT). In Cycle 1, patients are considered non-evaluable and will be replaced if they do not receive at least one dose of eribulin (unless due to a DLT), or if they discontinue from the study prior to completing all safety and toxicity evaluations for 3 weeks. These patients must be replaced unless accrual to the cohort has stopped due to a DLT. Nonevaluable patients will not be included in the cohort total for DLT evaluation.
a phase ib/ii study of
11.3 stratification factors

This is a Phase I/II trial. There will be no planned patient stratification factors.
a phase ib/ii study of
11.4 analysis of secondary endpoints

Efficacy - Although disease response is not a primary endpoint of the study, it will be assessed by clinical exam at defined time points (see table 9-1) and imaging after 6 weeks on study and then every 9 weeks until end of study treatment. Overall tumor response and time to progression will be assessed using RECIST 1.1 as described in Section 11. Response data will be correlated with dose as well as PD data in a descriptive manner.  
Correlative studies - The CTC studies, pharmacogenomics, and evaluation of archived tissue are exploratory. Results will be reported using descriptive statistics only.
a phase ib/ii study of
11.5 reporting and exclusions

11.5.1 Evaluation of toxicity.  
All patients will be evaluable for toxicity from the time of their first treatment with eribulin.
a phase ib/ii study of
11.5.2 evaluation of response

All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). [Note: By arbitrary convention, category 9 usually designates the "unknown" status of any type of data in a clinical database.]
All of the patients who met the eligibility criteria (with the possible exception of those who received no study medication) should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered to have a treatment failure (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific.  
All conclusions will be based on all eligible patients. Sub analyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified
(e.g., early death due to other reasons, early discontinuation of treatment, major protocol violations, etc.). However, these sub analyses will not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis will be clearly reported.  
The 95% confidence intervals will also be provided.
a phase ib/ii study of
12.0 multi-center guidelines

This study is a multiple-institution, investigator- sponsored trial (IST) coordinated by UCSF. Phase 1 will be conducted at UCSF. Phase 2 will be conducted at multiple-institutions. The UCSF
Coordinating Center provides administration, data management, and organizational support for the participating sites in the conduct of a multicenter clinical trial. The UCSF Coordinating Center will also coordinate quarterly conference calls with the participating sites to communicate the review of adverse events, safety data, and other study matters.  
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for monitoring its safety and progress at all participating sites. The Study Chair will conduct continuous review of data and subject safety and discuss each subject's treatment at monthly UCSF Site Committee meetings. The discussions are documented in the UCSF Site Committee meeting minutes.
a phase ib/ii study of
12.1 responsibilities of the coordinating/lead

The purpose of this section is to provide the regulatory guidelines needed for the conduct of multicenter investigator-initiated clinical trials where UCSF is the coordinating center. It is the Study Chair's responsibility to ensure that these guidelines are followed.
a phase ib/ii study of
12.1.1 oversight

The lead center will coordinate conference calls with participating sites approximately every 1 to 2 weeks to review adverse events, enrollment, safety data, cohort dose escalation, and other study matters. The dose level for ongoing enrollment will be confirmed for new patients scheduled at each site (see section 11 for more information).  
The lead center CRC will insure that participating sites are notified of safety events.  
Questions regarding the study or reporting of adverse events may be directed to the lead center CRC listed on Page 1 of this protocol.  
12.1.2 Protocol Distribution Upon approval by the coordinating center's IRB, the protocol will be distributed by the Study Chair or designee to the other participating sites via e-mail or private courier. The correspondence will include a description of changes made to the protocol and what action must be taken by the participating site.  
If necessary, the Study Chair will forward a copy of the protocol to the drug manufacturer (Eisai) in accordance with the manufacturer's submission requirements.  
12.1.3 Documentation of Distribution It is the responsibility of the Study Chair to maintain adequate files documenting the distribution of study documents as well as their receipt (when possible). The UCSF-HDFCCC recommends that the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., FDA, drug manufacturer, participating sites, etc.).  
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover letters, amendment outlines (summary of changes), etc., along with distribution documentation and (when available) documentation of receipt.  
Correspondence log: should be a brief list of all documents distributed including the date sent, recipient(s), and (if available) a tracking number and date received.  
At a minimum, the Study Chair must keep documentation of when and to whom the protocol and its updates and safety information are distributed.  
12.1.4 Documentation of Protocol Approvals Documentation of protocol approval at each participating sites will be maintained in a file by the Study Chair or designee; copies must also be provided to the centralized regulatory staff of the UCSFHDFCCC. It is the responsibility of the Study Chair to review these documents to ensure that participating sites are using the current protocol version.  
12.2 Responsibilities of other participating sites 12.2.1 Study Initiation Before the start of this study, the following documents must be submitted by the each site to the lead center CRC:
U.S. Food and Drug Administration (FDA) Form 1572, signed by the site's Principal Investigator.  
Current curricula vitae and medical licenses of the site's Principal Investigator and all coinvestigators.  
All investigators must also complete all regulatory documentation as required by local regulations.  
Written documentation of local IRB approval. Contact information (email, phone number, address) for the research pharmacist and designated contact person(s) (CRC and/or nurse) assigned to this study.  
12.2.2 Patient Enrollment
a phase ib/ii study of
refer to section 4.0

12.2.3 Study Drug Supply and Accountability Study drugs will be shipped from the drug manufacturer directly to the site. Each site will be responsible for drug accountability at their site. See Section 7.1 for specific instructions regarding study drug availability.  
12.2.4 Approval of Protocol and Amendments All protocol amendments must be approved by the participating site's IRB within 90 days of receipt. Failure to do so may result in the suspension of study activities at that site.  
Upon approval of the protocol or amendment by a participating site's IRB, a copy of the approval documentation must be submitted (electronic or hardcopy) to the Study Chair.
a phase ib/ii study of
13.0 data management

Case Report Form (CRF) and Source Documentation Study data will be entered into OnCore via electronic CRFs and electronic signatures.  
OnCore meets HIPAA guidelines.  
Source documentation will be kept in separate file folders for each subject.  
All source documentation and CRF data will be made available for monitoring/auditing.  
Regulatory Files Regulatory files will be maintained by the centralized regulatory office of the UCSF Helen Diller Family Comprehensive Cancer Center.  
Record Retention All study documentation will be archived as per sponsor/grantor requirements or as per institutional guidelines, whichever is greater.  
The University of California Office of the President (UCOP) recommends that study-related documents be maintained for at least 3 years after completion of the study.
a phase ib/ii study of
14.0 ethical aspects and regulatory

This study will be conducted in accordance with ICH GCP guidelines and the Declaration of Helsinki.
a phase ib/ii study of
14.2 scientific review

This study will be reviewed by the UCSF Comprehensive Cancer Center Protocol Review Committee (PRC) for scientific merit. After initial review and approval, the study will be reviewed at least once a year for scientific progress. Any changes to the protocol are to be reviewed and approved by the PRC.
a phase ib/ii study of
14.3 institutional review board /

The study will be reviewed by the Committee on Human Research (CHR), UCSF's IRB. After initial review and approval, the study will be reviewed at least once a year as per FDA regulations (21 CFR
56.109). Any changes to the protocol, consent form, and other associated documents are to be reviewed and approved by the CHR.  
It is the responsibility of the Principal Investigator to keep the CHR informed of the progress of the study, including changes to the protocol or consent form, exceptions or deviations from the protocol, and any new developments which may affect subject safety or willingness to participate.
a phase ib/ii study of
14.4 investigational new drug application

An IND will be filed with the FDA. For non-exempt studies, annual reports will be submitted to the FDA within 60 days of the anniversary date that the IND went into effect, as per FDA regulations (21 CFR 312.33).
a phase ib/ii study of
14.5 additional reporting requirements reporting

Although not considered an adverse experience, it is the responsibility of investigators or their designees to report any pregnancy in a patient or a male patient(s) partner (spontaneously reported to them) which occurs during the study or within 30 days of completing the study. Women who become pregnant must be followed to the completion/termination of the pregnancy. If the pregnancy continues to term, the outcome (health of infant) must also be reported to Eisai.
a phase ib/ii study of
15.0 adverse events and serious

Any unfavorable or unintended sign, symptom, or illness that develops or worsens during the course of the study (treatment and follow-up) regardless of causality. This includes abnormal clinical or laboratory findings.  
Laboratory AEs: Laboratory test value abnormalities are recorded as adverse events if they are clinically significant. Laboratory AEs are clinically significant if they are designated as serious, require treatment, cause dose modification/delay or premature withdrawal from the study, or place the subject at risk for other toxicity.  
Unexpected AEs: An AE is unexpected if it is not listed in the current labeling for the study drug (Investigator's Brochure, Package Insert, etc.), whether or not it has been previously reported. An unexpected AE may also be one that, although listed in the labeling, is greater in severity or occurs more frequently than expected.
a phase ib/ii study of
15.1.2 serious adverse events

A serious adverse event (SAE) is one that results in any of the following outcomes regardless of dose
(including overdose):
Death Life-threatening (places the subject, in the view of the investigator, at immediate risk of death from the reaction as it occurred)
Inpatient hospitalization or prolongs existing hospitalization, Persistent or significant disability/incapacity (a substantial disruption of a person's ability to conduct normal life functions),
Birth defect/congenital anomaly, Any important medical event that may not result in prior listed outcomes but, based upon appropriate medical judgment, may jeopardize the subject, and may require medical or surgical intervention to prevent one of the prior listed outcomes.
a phase ib/ii study of
15.2 adverse event grading

Severity of AEs will be graded as follows:
Grade 1 - Mild (no limitations) Grade 2 - Moderate (some limitations)
Grade 3 - Severe (requires medical attention; usual activities stop) Grade 4 - Life-threatening/disabling (requires immediate medical help) Grade 5 - Death Causality of AEs will be graded as follows:
Unrelated Unlikely related Possibly related Probably related Definitely related AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
a phase ib/ii study of
15.3 adverse event reporting period

Reportable AEs are normally those that occur at initiation of study drug and within 6 weeks after the last administration of study drug. Unresolved AEs (those that begin during the reporting period and extended past the 6 week period) should continue to be reported on if the condition worsens or results in death.  
AEs that begin after the end of the reporting period (after the 6 week period) are normally not reported, unless they are serious AND the primary investigator has reason to believe the event(s) might be related to study participation. During the last scheduled visit, the investigator should instruct the subject to report any event that the subject or the subject's referring physician believes might reasonably be related to study participation.
a phase ib/ii study of
15.4 adverse event reporting and

15.4.1 Oversight and Monitoring Plan The UCSF Helen Diller Family Comprehensive Cancer Center (UCSF-HDFCCC) Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for all UCSF-HDFCCC institutional clinical studies. A summary of DSMC activities for this study includes:
Review of subject data in each cohort Chairman will issue the approval to continue to the new dose level Monitoring every six months (depending on patient accrual)
Review of all serious adverse events Minimum of a yearly audit  
15.4.2 Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and patient safety at weekly study group or site committee meetings where the results of each patient's treatment are discussed and the discussion is documented in the minutes. The discussion will include for each dose level the number of patients, significant toxicities as described in the protocol, doses adjustments, and observed responses.  
The study coordinator will keep a log of subject(s) at each dose level in the UCSF-HDFCCC clinical trials management system (CTMS). DLTs will be documented in the CTMS. At the time of dose escalation, a written report will be submitted to the DSMC Chair outlining the cohort's dose, grade 3-5 AEs and SAE reports, and DLTs (if any) as described in the protocol. The report will be reviewed by the chairman or designee (maximum time 5 working days) and written authorization to proceed or a request for more information will be issued.  
15.4.3 Review and Oversight Requirements
a phase ib/ii study of
adverse event monitoring

Adverse Events (AEs) will be recorded on the CTMS. All grade 3-5 expected and unexpected AEs will be recorded and updated at each visit.
a phase ib/ii study of
serious adverse event reporting

Serious Adverse Event reporting will be in accordance with the UCSF Committee on Human Research (CHR) Regulations and Code of Federal Regulation (CFR) Title 21 Volume 5 Part 312.32. UCSF CHR website for guidance in reporting serious adverse events: http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.pdf FDA website for guidance in reporting serious adverse events:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.32 MedWatch forms and information:
http://www.fda.gov/medwatch/getforms.htm For studies conducted under an IND: Adverse events that are at least possibly related to the study and that are both serious and unexpected will be reported in writing to the FDA as soon as possible but no later than 15 days after first becoming aware of the event (21 CFR 312.32(c)). The sponsorinvestigator will use MedWatch FDA Form 3500A for mandatory reporting.  
Serious Adverse events will be reported on the MedWatch form. A copy of the MedWatch report and CHR forms must be sent to the DSMC . The date the SAE was sent to all required reporting agencies will be documented on the CTMS; hard copies of the report will be maintained in the regulatory files.  
All subjects/patients with serious adverse experiences must be followed up for outcome.  
If the SAE is death, and is determined to be possibly, probably or definitely related to the investigational drug or any research related procedure, the event must be reported to the DSMC Chair or his designee via phone or in person within 24 business hours of the Principal Investigator's awareness of the event. The reporting investigator or designee will confirm all verbal communication via e-mail and will copy the email to the DSMC Administrator and DSMC Coordinator.  
If any of the above actions occur in a multiple-institutional clinical trial coordinated by the UCSFHDFCCC, the CRC will ensure that all participating sites are notified.
a phase ib/ii study of
review of adverse event rates

If the study has an increase of grade 3 or 4 expected or unexpected AEs above the rate reported in the Investigational brochure or package insert, this will be reported to the DSMC at the time of identifying the increased rate.  
If at any time the Investigator stops enrollment or stops the study due to safety issues the DSMC
Chair and DSMC Administrator must be notified within 24 business hours via e-mail. The DSMC must receive a formal letter within 10 business days and the CHR must be notified.  
If any of the above actions occur in a multiple-institutional clinical trial coordinated by the UCSFHDFCCC, the CRC will ensure that all participating sites are notified.
a phase ib/ii study of
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Towle, M. J., K. A. Salvato, et al. (2001). "In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B." Cancer Res 61(3): 1013-1021.  
Twelves, C., J. Cortes, et al. (2010). "Phase III trials of eribulin mesylate (E7389) in extensively pretreated patients with locally recurrent or metastatic breast cancer." Clin Breast Cancer 10(2): 160-163.  
Vahdat, L. T., B. Pruitt, et al. (2009). "Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane."
J Clin Oncol 27(18): 2954-2961.  
Vergote, I., G. J. Rustin, et al. (2000). "Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup." J Natl Cancer Inst 92(18):
1534-1535.  
Wampler, M. A., C. Miaskowski, et al. (2006). "The modified total neuropathy score: a clinically feasible and valid measure of taxane-induced peripheral neuropathy in women with breast cancer." Supportive Oncology 4(8): W9-W16.  
Weigelt, B., A. M. Glas, et al. (2003). "Gene expression profiles of primary breast tumors maintained in distant metastases." Proc Natl Acad Sci U S A 100(26): 15901-15905.  
Wozniak, K. M., R. G. Lapidus, et al. (2010). "Assessment of neuropathy-inducing effects of eribulin mesylate versus paclitaxel and ixabepilone." European Society of Medical Oncology Annual Meeting.  
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                |                                                                                 |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|---------------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                               | Percent                                                                         | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence of  disease.            |                                                                                 |                                                                        |
| Normal activity. Fully active, able to                                                                                                                                                     |                                                            |                                                                                 |                                                                        |
| 0                                                                                                                                                                                          | carry on all pre-disease performance  without restriction. | 90                                                                              | Able to carry on normal activity; minor  signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able to  carry out work of a light or sedentary  nature (e.g., light housework, office  work). | 80                                                         | Normal activity with effort; some signs  or symptoms of disease.                |                                                                        |
| 1                                                                                                                                                                                          | 70                                                         | Cares for self, unable to carry on  normal activity or to do active work.       |                                                                        |
| In bed <50% of the time. Ambulatory  and capable of all self-care, but  unable to carry out any work  activities. Up and about more than  50% of waking hours.                             | 60                                                         | Requires occasional assistance, but is  able to care for most of his/her needs. |                                                                        |
| 2                                                                                                                                                                                          | Requires considerable assistance and                       |                                                                                 |                                                                        |
| 50                                                                                                                                                                                         | frequent medical care.                                     |                                                                                 |                                                                        |
| In bed >50% of the time. Capable of  only limited self-care, confined to bed  or chair more than 50% of waking  hours.                                                                     | 40                                                         | Disabled, requires special care and  assistance.                                |                                                                        |
| 3                                                                                                                                                                                          | 30                                                         | Severely disabled, hospitalization  indicated. Death not imminent.              |                                                                        |
| 20                                                                                                                                                                                         | Very sick, hospitalization indicated.  Death not imminent. |                                                                                 |                                                                        |
| 100% bedridden. Completely                                                                                                                                                                 |                                                            |                                                                                 |                                                                        |
| 4                                                                                                                                                                                          | disabled. Cannot carry on any selfcare. Totally confined to bed or chair.                                                            | 10                                                                              | Moribund, fatal processes progressing  rapidly.                        |
| 5                                                                                                                                                                                          | Dead.                                                      | 0                                                                               | Dead.                                                                  |
a phase ib/ii study of
appendix b

| Strong CYP3A4 Inhibitors that are prohibited during the study Amprenavir Atazanavir Clarithromycin Conivaptan Delavirdine Fosamprenavir Grapefruit juice Imatinib Indinavir Isoniazid Itraconazole Ketoconazole (oral) Nefazodone Nelfinavir Nevirapine   | Nicardipine Posaconazole Ritonavir Telithromycin   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|  
| Strong CYP3A4 Inducers that are prohibited during the study Barbiturates Carbamazepine Fosphenytoin Nafcillin  Nevirapine Oxcarbazepine Pentobarbital Phenobarbital  Phenytoin Primidone Rifabutin Rifampin   | Rifapentine St. John's wort   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|
| CYP3A4 Substrates (caution is advised) Astemizole Cisapride Opioid analgesics Pimozide Quinidine Tacrolimus                                                                                                   |                               |  
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF,
Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH;
LexiComp Inc. 2007: 1899-1912.  
This list is not comprehensive.  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at: http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.asp
modified total neuropathy score sheet
sensory symptoms

0=no symptoms 1=symptoms limited to the tips of fingers or toes 2=symptoms extend to ankle or wrist 3=symptoms extend to above ankle or above wrist to the level of knee or elbow 4=symptoms above knee or elbow and /or severe disabling symptoms that affect normal functioning and/or neuropathic pain that requires narcotic analgesia If symptoms are asymmetrical from side-to-side, grade the worst side (L/R).  
A. Paresthesias (tingling): _______________
B. Numbness ("dental work anesthesia"): ________________
C. Neuropathic pain (aching, burning, stabbing): __________________ D. Myalgias or Cramps: _________________
TOTAL SENSORY SYMPTOM SCORE (0-4)  
  
Use average score from A-D, round up to next whole number
modified total neuropathy score sheet
motor symptoms

0=no difficulty 1=with slight difficulty 2=with moderate difficulty 3=require some help or an assistive device 4=total loss of function A. Hand Dexterity (buttoning, writing, tying shoe laces, opening tight jars, or inserting key in lock)
____________
B. Foot Walking (unsteady on feet, walking on tip toes or on heels, or operating pedals in car)
________________
C. Legs Climbing steps, or standing up from a chair ____________
D. Arms Combing hair, or reaching up to a high shelf ___________
TOTAL MOTOR SYMPTOM SCORE (0-4)  
  
Use average score from A-D, round up to next whole number
modified total neuropathy score sheet
neurological examination sensory

0=normal 1=absent/decreased in index finger or great toe 2=absent/decreased up to ankle or wrist 3=absent/decreased up to elbow or knee 4=absent/decreased above the level of knee or elbow If symptoms are asymmetrical from side-to-side, grade the worst side (L/R).  
A. Pin level __________  
  
  
B. Vibration __________(*From quantitative vibration testing compared to norms in Bloom paper*)
TOTAL SENSORY SCORE (0-8)
modified total neuropathy score sheet
motor

0=normal (MMT ≥4+) 1=mild weakness, but can overcome some resistance (MMT 3+ to 4) 2=moderate weakness, can overcome gravity (MMT 3) 3=severe weakness with gravity eliminated (MMT 1 to 2)
4=paralysis (MMT 0) If symptoms are asymmetrical from side-to-side, grade the worst side (L/R).  
A. Ankle DF __________
B. Finger spread __________  
  
C. Wrist EXT __________
TOTAL MOTOR SCORE (0-4)  
  
  
Use score from weakest muscle group  
REFLEXES
L R
Biceps __________ __________ P=present Triceps __________ __________ PR=present with reinforcement Brachioradialis __________ __________ A=absent   
0=all reflexes normal (Biceps, Triceps, Brachioradialis, Knee, and ankle)
1=ankle reflex reduced 2=ankle reflex absent 3=ankle reflex absent, others reduced 4=all reflexes absent TOTAL REFLEX SCORE (0-4)
modified total neuropathy score sheet
eortc qlq-c30 (version 3)

We are interested in some things about you and your health. Please answer all of the questions yourself by circling the nmber that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential.  
Please fill in your initials: Your birthdate (Day, Month, Year):
ii 1111111  
| Today's date (Day, Month, Year):                      | 31                                                                    | ttttttt   | Not at   | A    | Quite   | Very   |
|-------------------------------------------------------|-----------------------------------------------------------------------|-----------|----------|------|---------|--------|
| AII                                                   | Little                                                                | a Bit     | Much     |      |         |        |
| Do you have any trouble doing strenuous activities,   |                                                                       |           |          |      |         |        |
| 1.                                                    | like carrying a heavy shopping bag or a suitcase?                     | l         | 2        | 3    | 4       |        |
| 2.                                                    | Do you have any trouble taking a long walk?                           | l         | 2        | 3    | 4       |        |
| 3.                                                    | Do you have any trouble taking a short walk outside of the house?     | l         | 2        | 3    | 4       |        |
| Do you need to stay in bed or a chair during the day? | 2                                                                     |           |          |      |         |        |
| 4.                                                    | 1                                                                     | 3         | 4        |      |         |        |
| 5.                                                    | Do you need help with eating, dressing, washing                       |           |          |      |         |        |
| yourself or using the toilet?                         | l                                                                     | 2         | 3        | 4    |         |        |
| During the past week:                                 | Not at                                                                | A         | Quite    | Very |         |        |
| All                                                   | Little                                                                | a Bit     | Much     |      |         |        |
| 6.                                                    | Were you limited in doing either your work or other daily activities? | 1         | 2        | 3    | 4       |        |
| Were you limited in pursuing your hobbies or other    |                                                                       |           |          |      |         |        |
| 7.                                                    | leisure time activities?                                              | l         | 2        | 3    | 4       |        |
| 8.                                                    | Were you short of breath?                                             | l         | 2        | 3    | 4       |        |
| 9.                                                    | Have you had pain?                                                    | 1         | 2        | 3    | 4       |        |
| 10. Did you need to rest?                             | l                                                                     | 2         | 3        | 4    |         |        |
| 1. Have you had trouble sleeping?                     | 2                                                                     |           |          |      |         |        |
| l                                                     | 3                                                                     | 4         |          |      |         |        |
| 12. Have you felt weak?                               | l                                                                     | 2         | 3        | 4    |         |        |
| 13. Have you lacked appetite?                         | l                                                                     | 2         | 3        | 4    |         |        |
| 14. Have you felt nauseated?                          | l                                                                     | 2         | 3        | 4    |         |        |
| 15. Have you vomited?                                 | 1                                                                     | 2         | 3        | 4    |         |        |
| 16. Have you been constipated?                        | 1                                                                     | 2         | 3        | 4    |         |        |
| Please go on to the next page.                        |                                                                       |           |          |      |         |        |  
During the past week:  
  
17. Have you had diarrhea?
18. Were you tired?  
19. Did pain interfere with your daily activities? 20. Have you had difficulty in concentrating on things, like reading a newspaper or watching television?  
  
21. Did you feel tense? 2. Did you worry?  
23. Did you feel imtable?  
24. Did you feel depressed?  
25. Have you had difficulty remembering things? 26. Has your physical condition or medical treatment interfered with your family life?  
27. Has your physical condition or medical treatment interfered with your social activities?  
  
1  
 1  
  
Very Much  
| 4   |
|-----|  
| 4   |
|-----|  
3  
  
3  
| 1   |
|-----|  
  
| 2   |
|-----|
| 2   |  
  
4  
1  
   
Not at  
  
ENGLISH  
  
29. How would you rate your overall health during the past week?  
  
2 3  
  
  
7 4 s 6 Very poor Excellent 30. How would you rate your overall quality of life during the past week?  
7 1 2 3 4 s 6 Very poor Excellent
© Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0  
| 1   |
|-----|  
2 3 4  
| 1   |
|-----|  
2 4  
| 3   |
|-----|  
| l   |
|-----|  
2 3 4 3 4 3 4 4 4 3 4 3 3 4 For the following questions please circle the number between 1 and 7 that best applies to you 2  
| l   |
|-----|  
  
2 2 2 3 i  
| l   |
|-----|
| l   |  
caused you financial difficulties?  
28. Has your physical condition or medical treatment  
| 2   |
|-----|
| 2   |
modified total neuropathy score sheet
fact/gog-ntx (version 4)

Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| ADDITIONAL CONCERNS    | Not at                                                 | A little   | Some-   | Quite   | Very   |    |
|------------------------|--------------------------------------------------------|------------|---------|---------|--------|----|
| all                    | bit                                                    | what       | a bit   | much    |        |    |
| NTX                    | I have numbness or tingling in my hands.               | 2          |         |         |        |    |
| 0                      | 1                                                      | 3          | 4       |         |        |    |
| NIX                    | I have numbness or tingling in my feet .               | 0          | 1       | 2       | 3      | 4  |
| XIN
3                        | I feel discomfort in my hands.                         | 1          | 2       | 3       |        |    |
| 0                      | 4                                                      |            |         |         |        |    |
| xx                     | I feel discomfort in my feet .                         | 2          |         |         |        |    |
| 0                      | 1                                                      | 3          | 4       |         |        |    |
| k  
REF                        | I have joint pain or muscle cramps                     | 0          | l       | 2       | 3      | 4  |
| H12                    | I feel weak all over .                                 | 0          | 2       |         |        |    |
| 1                      | 3                                                      | 4          |         |         |        |    |
| I have trouble hearing |                                                        |            |         |         |        |    |
| xxx  
1                        | 0                                                      | 1          | 2       | 3       | 4      |    |
| NIX                    | I get a ringing or buzzing in my ears.                 | 0          | l       | 2       | 3      | 4  |
| xx                     | I have trouble buttoning buttons .                     | 2          |         |         |        |    |
| 0                      | 1                                                      | 3          | 4       |         |        |    |
| NTX                    | I have trouble feeling the shape of small objects when |            |         |         |        |    |
| they are in my hand    | 0                                                      | l          | 2       | 3       | 4      |    |
| I have trouble walking |                                                        |            |         |         |        |    |
| And                    | 0                                                      | l          | 2       | 3       | 4      |    |
modified total neuropathy score sheet
appendix f

Correlative Studies All specimens will be de-identified prior to sending. Only a study ID \# will be on the collection tubes.
modified total neuropathy score sheet
pharmacokinetics-phase ia only

Whole blood for pharmacokinetic assessments of pazopanib and PCI24781 will be drawn in 6 mL tubes on the following schedule: Phase Ia: Cycle 1 Day 1: pre-dose, at the end of eribulin infusion, and at 15 min, 30 min, hour 1, 2, 3, 4, 6 and 8 Handling of Specimens(s) - Standard phlebotomy handling ALL required labels will be provided by a third-party vendor contracted by the sponsor. Labels will come **pre-filled** with the following information:
Protocol No.: **11996**  
Treatment: **Cohort/Dose level**
Nominal Time Point: **Predose, 1, 2 hr, etc.**
modified total neuropathy score sheet
sample type blood plasma (primary)

The SITE is then responsible for entering the following information on each sample label:
Patient ID Number  
Patient Initials
ALL blood and plasma collection and storage tubes should be labeled **PRIOR** to sample collection.  
1. Fill an ice bucket with a sufficient amount of ice to completely immerse all tubes before blood draw.  
2. Collect approximately 6 mL of whole blood into a pre-chilled 6-mL Na-Heparin tube.  
3. Gently invert the tube 3-5 times and immerse it into the ice immediately to prevent possible compound degradation at room temperature.  
4. Record drawing time immediately before proceeding to the next step.  
5. Within 15 min. of blood collection, the sample must be processed by centrifuging at 1,500 g
(3,000 rpm) for 10 min to obtain plasma.  
6. Transfer approximately 1.5 mL plasma into each of the two clean, pre-labeled polypropylene tubes (primary and secondary). Immerse both tubes into the ice immediately to prevent possible compound degradation at room temperature. Note, if short on plasma, ensure that the primary sample tube contains 1.5 mL
7. Transfer both polypropylene tubes into a –70oC/–80oC freezer (within 1 hour of collection),
where they will remain stored until shipping.  
8. Immediately record time of samples' entry into the freezer.
NOTE: All secondary (backup) samples will be maintained at the collecting site until they are requested by the sponsor to be sent to the bioanalytical laboratory.  
Site(s) Performing Correlative Study - XenoBiotic Laboratories, Inc.  
Shipping of Specimen(s) –  
  
Blood will be processed as above, frozen and shipped on dry ice by overnight mail on MondayWednesday to:
Notification on the day of shipping should be sent to:
Do not ship samples the day before a holiday.  
Always ship the primary sample set to the bioanalytical lab first per pre-agreed shipping schedule.  
All secondary (used as backup) samples will be stored in a –70oC/–80oC freezer at the collecting site until shipping is requested by the sponsor.  
Arrange sample pick-up(s) (e.g., World Courier)
XBL must be contacted via email at least one working day prior to shipment and confirmation of receipt by XBL must be documented at the clinical site.  
If you do not hear from XBL within 2-3 working days of shipping, please contact the person listed in **above** immediately to ascertain the delivery status of the samples.
modified total neuropathy score sheet
shipping process

1. Obtain 20 lbs of dry ice pellets. Use as much dry ice as possible to help safeguard against any possible delays.  
2. Use a Styrofoam box, for example, a 19" x 19" x 12". Use a larger one if multiple samples are being shipped.  
3. Place a 4" layer of dry ice in the bottom of the Styrofoam box. Package the samples the day of shipping to maximize the effectiveness of the dry ice pellets.  
4. Wrap the frozen samples in bundles using an elastic band and place the sample bundles in a plastic freezer bag.  
5. Use newspaper or other similar material to insulate the bagged sample bundles from direct contact with the dry ice.  
6. Place the sample bundles in the Styrofoam box and fill the excess space with the remaining dry ice pellets.  
7. Record the estimated weight of the dry ice used per box.
8. Place the lid on the Styrofoam box and seal around the edges completely with tape.  
9. Place the Styrofoam box in a larger cardboard shipping carton. Tape the plastic bag or plastic sleeve that contains essential sample documents from the site on top of the Styrofoam box.  
10. Seal the shipping carton securely with tape.
modified total neuropathy score sheet
labeling the cardboard box

1. Indicate return address and contact person on each carton. 2. Mark the outside of the shipping cartons with tally number e.g., - Box 1 of 3 boxes, Box 2 of 3 boxes, and Box 3 of 3 boxes.  
3. Affix the **Biological Substance B** label with the information below to the outside of each box:
- One (1) carbon dioxide label with the weight included. Example:
Carbon Dioxide Solid UN-1845  
 Class 9 PKG GR III
KG _______________________
- Two (2) internationally recognized dry ice symbols (Class 9) - one on either side of  
  
the box. Example:
- One (1) **KEEP FROZEN** label
modified total neuropathy score sheet
sample collection documents to accompany

A copy of the completed specimen inventory log(s) (i.e., a copy of the completed CRF
Specimen Collection page).  
Sponsor Name: **Eisai**
Any missing information may cause a delay in analysis.  
Please notify XBL by email or fax immediately after the samples have been collected by the courier.  
Provide the following information to XBL:  
Name of courier or transport company (i.e., World Courier)
Date and time the shipment left your premises The airway bill number
modified total neuropathy score sheet
single-nucleotide polymorphisms

One 10 mL purple top tube will be collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment.  
DNA extraction and analysis for three novel candidate genes which may relate to development of peripheral neuropathy, FZD3, FGD4 and EPHA5 will be performed. Other exploratory analysis may also be performed. Handling of Specimens(s) - Standard phlebotomy handling Sites Performing Correlative Study - Deanna Kroetz laboratory, UCSF
Shipping of Specimen(s) - UCSF: No shipment is required. Samples will be hand-delivered by courier at 4C and shipped on cold packat room temperature to the Kroetz laboratory in batches. Outside sites: Samples will be stored at 4C and shipped on cold pack at room temperature to the  
  
Kroetz laboratory:
modified total neuropathy score sheet
genome scan

One 10 mL purple top tube will be collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment.  
DNA extraction and analysis will be done by the DNA bank at UCSF, and then samples will be sent to Dr. Pui-Yan Kwok's laboratory for genomic profile. Handling of Specimens(s) - Standard phlebotomy handling Sites Performing Correlative Study - Pui-Yan Kwok laboratory, CVRI, UCSF
Shipping of Specimen(s) –
UCSF: No shipment is required. Samples will be hand-delivered by courier at room temperature to the DNA bank laboratory immediately after they are obtained and processed immediately. If unable to be sent immediately, samples will be frozen and shipped on dry ice. Outside sites: Samples will be frozen and will be on shipped on dry ice by overnight mail to:  
  
  
 Shigeshi "Shag" Yamamoto Circulating Tumor Cells 2 CellSave tubes and 1 purple top tube will be collected at baseline, either during screening assessments or Cycle 1 Day 1 prior to treatment. If this first sample has ≥ 5 CTC/mL, then on Cycle 2 Day 1, 1 CellSave and 1 purple top tube will be collected for CTC enumeration and aCGH/gene expression. 2 CellSave tubes and 1 purple top tube should be obtained at end of study if at all possible.  
7.5 mL of blood is required per CellSave tube, it is critical that the tube be completely filled.  
10mL is required in each purple top tube. One CellSave tube will be used for CTC enumeration, the second CellSave tube will be used for sorting and WGA with CGH/sequencing. The purple top tube will also be used for gene expression if there is adequate sample.  
Handling of Specimens(s) - Standard phlebotomy handling Site(s) Performing Correlative Study - John Park MD laboratory, UCSF
Shipping of Specimen(s) –
UCSF: No shipment is required. Samples will be hand-delivered at room temperature to the Park laboratory immediately after they are obtained and processed immediately. Outside sites: Blood will be shipped at room temperature by overnight mail to: Park Lab Notification on the day of shipping should be sent to:
Special instructions will be provided for Friday shipping.  
Archived Tissue Analysis Once a patient is consented for this study, they will also sign a Tumor Specimen Release Form.  
Clinical research coordinators will request FFPE (formalin-fixed paraffin embedded) archived tumor blocks from prior surgery or biopsies along with stained H&E slides, for all patients. These specimens are not required and should not delay enrollment. These specimens will become the property of  
  
UCSF Cancer Center and will be stored at the Cancer Center Tissue Core at UCSF under direction of Dr. Stöppler.  
Quality of life EORTC QLQ-30, found in Appendix C, will be self-administered to each patient on the following schedule: Prior to starting treatment (within 7 days of cycle 1 day 1), then at 6 weeks, 3 months, 12 months, 18 months, 24 months, and/or study termination. Questionnaires may be mailed, emailed, or faxed in advance to patients and/or completed during visits. Questionnaires must be completed by the patient and can be completed up to 7 days prior to drug administration. Translation services may be used for completion of questionnaires. Results will be compiled by research staff.  
Neuropathy measurements 1. 10-point modified neuropathy score (mTNS), found in Appendix D, will be performed by research staff at the start of each cycle and at study termination. Results will be compiled by research staff. 2. FACT/GOG-NTX questionnaire, found in Appendix E, will be self-administered to each patient on the following schedule: at the start of each cycle and at study termination. Questionnaires may be mailed, emailed, or faxed in advance to patients and/or completed during visits. Questionnaires must be completed by the patient and can be completed up to 7 days prior to drug administration.  
Translation services may be used for completion of questionnaires. Results will be compiled by research staff.