A Phase I Trial Evaluating mFOLFOX6 and Avastin With Nexavar as First-Line Treatment for Metastatic Colorectal Cancer

• Sponsor: Accelerated Community Oncology Research Network (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00779311
• Collaborator: Bayer (Industry)
• Enrollment: 8
• Locations: 3
• Arm: 1
• Duration (Months): 28.9
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This research study is being performed at approximately 3 sites associated with Accelerated Community Oncology Research Network, Inc. (ACORN). Approximately 45 subjects will take part in this study.

In this study, everyone will receive the same dose of mFOLFOX6 and Avastin. There will be five groups of subjects. Each group of subjects will receive a higher dose of Nexavar than the previous group. This will continue until a subject group has a major side effects from the dose they are given. This is so that the sponsor can determine the highest dose of Nexavar that can be used with mFOLFOX6 and AVastin (this is called the maximum tolerated dose or MTD).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: sorafenib; Drug: bevacizumab; Drug: mFOLFOX6 regimen	Phase 1

Detailed Description

This is an investigator-initiated, multicenter, network, Phase 1, open-label, dose-ranging study. The maximum sample size will be 45 patients (up to 30 patients for determining MTD at Phase I, and an additional 15 patients to provide for estimate of progression free survival). All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle. Treatment cycle length is 2 weeks (Q2W). Sorafenib will be administered daily throughout treatment beginning on day 1.

Dose limiting toxicity will be defined as any grade 4 hematologic event or any grade 3 or 4 non-hematologic event occurring during cycle 1 or 2 that is attributable to sorafenib or the combination. The following events are excluded from this definition: grade 3 nausea and/or vomiting responsive to antiemetics; grade 3 fever or infection; grade 3 diarrhea responsive to antidiarrheal therapy.

Three patients will be enrolled at a dose level and observed for dose-limiting toxicities (DLTs) for 2 cycles of treatment. Dose escalation for sorafenib will depend on the number of patients experiencing DLT(s) as follows:

• If 0/3 patients experience DLT(s), then 3 more patients are treated at the next higher dose.

• If 1/3 patients experiences DLT(s), then 3 more patients are enrolled at that dose. If 1/6 of the patients treated at that dose experiences DLT(s), then the next cohort is treated at the next higher dose. However, if ≥2/6 patients experience DLT(s) at that dose, then the MTD is considered to have been exceeded. At that point, 3 more patients are treated at the next lower dose, unless 6 have already been treated at that lower dose.

• If ≥2/3 patients experience DLT(s) at a dose, then 3 more patients are enrolled at the next lower dose unless 6 patients have already been treated at that dose.

Dose escalation will continue until the MTD is determined or until all dose levels have been completed. The MTD is defined as the dose at which ≤1 of 6 patients experience DLT(s), and above which ≥2 of 6 patients experience DLT(s). If the MTD is at Dose Level 2 (or lower), then the study will be terminated and no further patients will be enrolled.

Once the MTD for sorafenib combined with mFOLFOX6 and bevacizumab has been determined, an additional 15 patients with mCRC will be enrolled into an extension of the Phase 1 study. These patients will be treated at the MTD for sorafenib with the combination therapy to assess PFS and safety of the regimen as first-line therapy in mCRC. All patients will be eligible for indefinite treatment in the absence of disease progression or unacceptable toxicity.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Trial Evaluating mFOLFOX6 and Avastin With Nexavar as First-Line Treatment for Metastatic Colorectal Cancer
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Experimenal All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle. Sorafenib will be administered daily throughout treatment beginning on day 1

Drug: sorafenib; Sorafenib will be administered daily starting day 1 at 200mg QOD at Dose Level 1; 200mg/day at Dose Level 2; 200mg BID (5 days on/ 2 days off) at Dose Level 3; 200mg BID at Dose Level 4; and 400mg BID at Dose Level 5.; Other Names: Nexavar ; Drug: bevacizumab; Bevacizumab will be administered as 5mg/kg IV on Day 1 of each treatment cycle.; Other Names: Avastin ; Drug: mFOLFOX6 regimen; The mFOLFOX6 regimen will be administered on Day 1 of each treatment cycle. This regimen consists of oxaliplatin 85 mg/m2 IV given over 2 hours, leucovorin 400 mg/m2 IV given over 2 hours, and fluorouracil 400 mg/m2 IV bolus, followed by fluorouracil 1200 mg/m2 per day for 2 days continuous infusion.

Outcome Measures

Primary Outcome Measures

1. Determination of the Maximum Tolerated Dose (MTD) of Sorafenib When Given in Combination With mFOLFOX6 and Bevacizumab [MTD was assessed during the first 2 cycles of treatment (i.e., the first 4 weeks of treatment since cycle length is 2 weeks)]

   The MTD of sorafenib was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose depends on the frequency of dose limiting toxicities (DLT) at each dosage. If 0 out of 3 patients experience a DLT at a given dosage level, 3 patients will be enrolled at the next dosage level. If greater than or equal to 2 patients experience a DLT at a given dosage level, dosage escalation will be stopped. If 1 out of 3 patients experience a DLT at a given dosage level, 3 patients are enrolled at the same dosage level.

Secondary Outcome Measures

1. Determination of Progression Free Survival (PFS) Among Patients on This Regimen [PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first.]

   PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.

2. Determination of Quality of Life (QoL) as Indicated by Patient Care Monitor (PCM) Data Among Patients on This Regimen [The PCM questionnaire was administered on day 1 of each cycle (approximately every 2 weeks) during study treatment.]

   The subject answers questions from the following 6 categories: general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation. Each question has a scale from 0 through 10, where 0 is not a problem and 10 is as bad as possible. The frequency of patient reported severe (rated as >=7) symptoms reported from the set of symptoms assessed by the PCM.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• No prior chemotherapy for metastatic disease.

• Histologically proven colorectal carcinoma.

• Measurable disease by RECIST criteria.

• Age: at least 18 years.

• ECOG performance status of 0 or 1 at study entry.

• Adequate bone marrow, liver and renal function at study entry as assessed by the following:

• Hemoglobin >9.0 g/dL.

• ANC ≥1500/mm3.

• Platelet count ≥100,000/mm3.

• Total bilirubin ≤1.5 times x ULN.

• ALT and AST ≤2.5 × ULN (≤5 × ULN for patients with liver involvement).

• Creatinine ≤1.5 × ULN.

• INR <1.5 or a PT/PTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate after discussion with ACORN. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.

• Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days prior to the start of treatment.

• Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Patients should use adequate birth control for at least 3 months after the last administration of sorafenib.

• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

Exclusion Criteria:

• Prior use of bevacizumab.

• Neuropathy ≥ Grade 2 per CTCAE v3.0.

• Diarrhea ≥ Grade 2 per CTCAE v3.0 within 4 weeks of study treatment start.

• ECOG performance status ≥ 2.

• Proteinuria at baseline: patients discovered to have > 2+ proteinuria at baseline should undergo a 24 hour urine collection and must demonstrate < 1 gram of protein in 24 hours to be eligible.

• Active malignancy other than mCRC (except non-melanoma skin cancer; in situ carcinoma of the cervix; in situ carcinoma of the breast) within the last 5 years.

• Treatment with radiotherapy within 2 weeks of enrollment.

• Cardiac disease: Congestive heart failure > Class II NYHA. Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months.

• Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/ MRI of the brain to exclude brain metastasis.

• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

• Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management.

• Known human immunodeficiency virus infection or chronic Hepatitis B or C.

• Active clinically serious infection > Grade 2 per CTCAE v3.0.

• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.

• Pulmonary hemorrhage/bleeding event ≥ Grade 2 per CTCAE v3.0 within 4 weeks of study treatment start.

• Any other hemorrhage/bleeding event ≥ Grade 3 per CTCAE v3.0 within 4 weeks of study treatment start.

• Serious non-healing wound, ulcer, or bone fracture.

• Evidence or history of bleeding diathesis or coagulopathy.

• Major surgery, open biopsy or significant traumatic injury within 4 weeks of study treatment start; fine needle aspiration or central venous line placement for chemotherapy administration within 7 days of study treatment start.

• Use of daily corticosteroids, St. John's Wort, rifampin (rifampicin), phenytoin, carbamazepine, phenobarbital, ketoconazole. Dexamethasone may only be used as an antiemetic or as a premedication for a bevacizumab hypersensitivity reaction during participation in this study.

• Known or suspected allergy to sorafenib or any other agent given in the course of this trial.

• Any condition that impairs patient's ability to swallow whole pills.

• Any malabsorption problem.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Georgia Cancer Care	Macon	Georgia	United States	31201
2	Hematology Oncology Centers of the Northern Rockies	Billings	Montana	United States	59101
3	The West Clinic	Memphis	Tennessee	United States	38120

Sponsors and Collaborators

• Accelerated Community Oncology Research Network
• Bayer

Investigators

• Principal Investigator: Fred Schnell, MD, Central Georgia Cancer Care

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Accelerated Community Oncology Research Network
• ClinicalTrials.gov Identifier: NCT00779311
• Other Study ID Numbers: AFMSMCRC0706
• First Posted: Oct 24, 2008
• Last Update Posted: Nov 2, 2011
• Last Verified: Oct 1, 2011

• Keywords provided by Accelerated Community Oncology Research Network: Metastatic Colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Bevacizumab; Sorafenib

Study Results

Participant Flow

Recruitment Details	Three community oncology research sites across the US within the ACORN Network participated in this study. Enrollment started in October 2008 and was closed early in April 2010 due to two subjects experiencing DLT at the lowest dose level.
Pre-assignment Detail	Informed consent was obtained from all subjects. All subjects underwent a screening period that could last up to 4 weeks during which pre-study assessments were completed. All subjects received mFOLFOX6, bevacizumab, and sorafenib. Subjects were assigned to a Dosage Level at the time of enrollment.

Arm/Group Title	Dose Level (DL) 1 for MTD Determination	Dose Level (DL) 2 for MTD Determination	Dose Level (DL) 3 for MTD Determination	Dose Level (DL) 4 for MTD Determination	Dose Level (DL) 5 for MTD Determination
Arm/Group Description	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every other day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day, 5 days on followed by 2 days off.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 400mg twice a day.
Period Title: Overall Study
STARTED	8	0	0	0	0
Dose Limiting Toxicity (DLT) Evaluation	6	0	0	0	0
COMPLETED	8	0	0	0	0
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Dose Level (DL) 1 for MTD Determination	Dose Level (DL) 2 for MTD Determination	Dose Level (DL) 3 for MTD Determination	Dose Level (DL) 4 for MTD Determination	Dose Level (DL) 5 for MTD Determination	Total
Arm/Group Description	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every other day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day, 5 days on followed by 2 days off.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 400mg twice a day.	Total of all reporting groups
Overall Participants	8	0	0	0	0	8
Age (participants) [Number]
<=18 years	0 0%	0 NaN
Between 18 and 65 years	3 37.5%	3 Infinity
>=65 years	5 62.5%	5 Infinity
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.0 (11.40)	62.0 (11.40)
Gender (participants) [Number]
Female	3 37.5%	3 Infinity
Male	5 62.5%	5 Infinity
Region of Enrollment (participants) [Number]
United States	8 100%	8 Infinity

Outcome Measures

1. Primary Outcome

Title	Determination of the Maximum Tolerated Dose (MTD) of Sorafenib When Given in Combination With mFOLFOX6 and Bevacizumab
Description	The MTD of sorafenib was determined using a standard 3 + 3 dose escalation cohort design. The total sample and the number of patients who receive each dose depends on the frequency of dose limiting toxicities (DLT) at each dosage. If 0 out of 3 patients experience a DLT at a given dosage level, 3 patients will be enrolled at the next dosage level. If greater than or equal to 2 patients experience a DLT at a given dosage level, dosage escalation will be stopped. If 1 out of 3 patients experience a DLT at a given dosage level, 3 patients are enrolled at the same dosage level.
Time Frame	MTD was assessed during the first 2 cycles of treatment (i.e., the first 4 weeks of treatment since cycle length is 2 weeks)

Outcome Measure Data

Analysis Population Description

3 patients (pts) were enrolled at DL 1 with 1/3 experiencing DLT, so 3 additional pts were enrolled at DL 1. 2 of those additional pts were not evaluable for DLT assessment and were replaced. 2 more pts were enrolled for a total of 8 pts, and 1 of these pts experienced a DLT. All of the 8 pts enrolled received sorafenib at DL 1.

Arm/Group Title	Dose Level (DL) 1 for MTD Determination	Dose Level (DL) 2 for MTD Determination	Dose Level (DL) 3 for MTD Determination	Dose Level (DL) 4 for MTD Determination	Dose Level (DL) 5 for MTD Determination
Arm/Group Description	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every other day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day, 5 days on followed by 2 days off.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 400mg twice a day.
Measure Participants	8	0	0	0	0
Number [mg every other day]	200

2. Secondary Outcome

Title	Determination of Progression Free Survival (PFS) Among Patients on This Regimen
Description	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first.
Time Frame	PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level (DL) 1 for MTD Determination	Dose Level (DL) 2 for MTD Determination	Dose Level (DL) 3 for MTD Determination	Dose Level (DL) 4 for MTD Determination	Dose Level (DL) 5 for MTD Determination
Arm/Group Description	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every other day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day, 5 days on followed by 2 days off.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 400mg twice a day.
Measure Participants	8	0	0	0	0
Median (95% Confidence Interval) [Months]	10.61

3. Secondary Outcome

Title	Determination of Quality of Life (QoL) as Indicated by Patient Care Monitor (PCM) Data Among Patients on This Regimen
Description	The subject answers questions from the following 6 categories: general physical symptoms, treatment side effects, distress, despair, impaired performance, and impaired ambulation. Each question has a scale from 0 through 10, where 0 is not a problem and 10 is as bad as possible. The frequency of patient reported severe (rated as >=7) symptoms reported from the set of symptoms assessed by the PCM.
Time Frame	The PCM questionnaire was administered on day 1 of each cycle (approximately every 2 weeks) during study treatment.

Outcome Measure Data

Analysis Population Description

The number of patients out of the total sample of 8 patients who reported severe (rated as >=7) symptoms as assessed by the PCM. Symptoms with 0 patients reporting severe symptoms have been omitted.

Arm/Group Title	Dose Level (DL) 1 for MTD Determination	Dose Level (DL) 2 for MTD Determination	Dose Level (DL) 3 for MTD Determination	Dose Level (DL) 4 for MTD Determination	Dose Level (DL) 5 for MTD Determination
Arm/Group Description	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every other day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day, 5 days on followed by 2 days off.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day.	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 400mg twice a day.
Measure Participants	8	0	0	0	0
Fatigue	3 37.5%
Change in taste	2 25%
Mouth sores/ulcers	1 12.5%
Sore throat	1 12.5%
Trouble swallowing	1 12.5%
Day sweat	1 12.5%
Night sweat	1 12.5%
Reduced sexual enjoyment, interest, or performance	2 25%
Heartburn	1 12.5%
Nausea	2 25%
Problem with urination	1 12.5%
Bruising	1 12.5%
New lump/mass	1 12.5%
Hair loss	1 12.5%
Nails change	1 12.5%
Joint pain	2 25%
Muscle aches	2 25%
Weakness of body parts	2 25%
Burning sensation in hands or feet	2 25%
Numbness/tingling	2 25%
Trouble sleeping at night	2 25%
Pain	1 12.5%
Attend paid job	2 25%
Attend social activity	1 12.5%
Hard work or activity	2 25%
Household work	1 12.5%
Light work or activity	1 12.5%
Run	2 25%
Walk	1 12.5%
Crying/feeling like crying	1 12.5%
Feeling helpless	1 12.5%
Feeling hopeless	1 12.5%
Lost interest in people	1 12.5%
Nervous, tense, anxious	2 25%
Worry	2 25%

Adverse Events

Time Frame	Adverse events were collected beginning on day 1 of study treatment until one month after the end of study treatment.
Adverse Event Reporting Description	Systematic Assessment - subjects were assessed for adverse events on day 1 of each cycle (every other week) by either the research coordinator, treating physician, or other appropriate sub-investigator.
Arm/Group Title	Dose Level (DL) 1 for MTD Determination		Dose Level (DL) 2 for MTD Determination		Dose Level (DL) 3 for MTD Determination		Dose Level (DL) 4 for MTD Determination		Dose Level (DL) 5 for MTD Determination
Arm/Group Description	All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every other day.		All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg every day.		All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day, 5 days on followed by 2 days off.		All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 200mg twice a day.		All eligible patients will receive the mFOLFOX6 regimen at full dose followed by IV bevacizumab 5mg/kg on Day 1 of each treatment cycle, and sorafenib 400mg twice a day.
All Cause Mortality
	Dose Level (DL) 1 for MTD Determination		Dose Level (DL) 2 for MTD Determination		Dose Level (DL) 3 for MTD Determination		Dose Level (DL) 4 for MTD Determination		Dose Level (DL) 5 for MTD Determination
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dose Level (DL) 1 for MTD Determination		Dose Level (DL) 2 for MTD Determination		Dose Level (DL) 3 for MTD Determination		Dose Level (DL) 4 for MTD Determination		Dose Level (DL) 5 for MTD Determination
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Gastrointestinal disorders
Diarrhea	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
General disorders
Chest pain	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Infections and infestations
Gastroenteritis	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Pneumonia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Nervous system disorders
Dysgeusia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Lethargy	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Renal and urinary disorders
Renal failure acute	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Pulmonary embolism	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Dose Level (DL) 1 for MTD Determination		Dose Level (DL) 2 for MTD Determination		Dose Level (DL) 3 for MTD Determination		Dose Level (DL) 4 for MTD Determination		Dose Level (DL) 5 for MTD Determination
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/8 (100%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Blood and lymphatic system disorders
Anemia	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Neutropenia	5/8 (62.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Thrombocytopenia	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Eye disorders
Lacrimation increased	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Gastrointestinal disorders
Abdominal hernia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Abdominal pain	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Constipation	5/8 (62.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Diarrhea	4/8 (50%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Dry mouth	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Dyspepsia	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Dysphagia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Mouth ulceration	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Nausea	5/8 (62.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Proctalgia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Rectal hemorrhage	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Stomatitis	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Vomiting	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
General disorders
Chest discomfort	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Chest pain	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Chills	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Fatigue	5/8 (62.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Mucosal inflammation	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Pyrexia	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Temperature intolerance	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Thrombosis in device	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Infections and infestations
Fungal infection	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Laryngitis bacterial	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Sinusitis	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Tooth abscess	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Upper respiratory tract infection	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Urinary tract infection	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Investigations
Blood albumin decreased	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Blood creatinine increased	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Blood urea increased	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Weight decreased	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Metabolism and nutrition disorders
Decreased appetite	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hyperglycemia	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hyperkalemia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hypoalbuminemia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hypokalemia	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hypomagnesemia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hyponatremia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hypophosphatemia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Musculoskeletal and connective tissue disorders
Arthralgia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Pain in extremity	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Nervous system disorders
Dizziness	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Dysesthesia	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Dysgeusia	4/8 (50%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Headache	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Neuropathy peripheral	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Psychiatric disorders
Anxiety	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Insomnia	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Cough	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Dyspnea	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Epistaxis	4/8 (50%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Hiccups	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Pulmonary embolism	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Respiratory tract congestion	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Skin and subcutaneous tissue disorders
Alopecia	3/8 (37.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Cold sweat	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Increased tendency to bruise	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Nail disorder	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Palmar-plantar erythrodysesthesia syndrome	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Pruritis	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Rash	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Vascular disorders
Hypertension	2/8 (25%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Orthostatic hypotension	1/8 (12.5%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Peripheral coldness	4/8 (50%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

Early termination due to the MTD determined to be Dose Level 1, leading to a small number of subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Prior to publication or presentation of Sponsored Research results, Researcher agrees to provide Bayer with such presentation, abstract, or manuscript at least 30 days prior to its presentation or submission for the sole purpose of allowing Bayer to redact Confidential Information and protect any existing or future patents.