Sorafenib and Everolimus in Treating Patients With Relapsed or Refractory Lymphoma or Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00474929
• Collaborator: University of Iowa (Other)
• Enrollment: 103
• Locations: 2
• Arms: 2
• Actual Duration (Months): 143.3
• Patients Per Site: 51.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

RATIONALE: Sorafenib and everolimus may stop the growth of cancer cells by blocking blood flow to the cancer and by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I/II trial is studying the side effects and best dose of sorafenib and everolimus and to see how well they work in treating patients with relapsed or refractory non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm	Drug: RAD001; Drug: Sorafenib	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

• Determine the maximum tolerated dose (MTD) of sorafenib tosylate and everolimus in patients with relapsed or refractory non-Hodgkin's lymphoma, Hodgkin's lymphoma, or multiple myeloma.

• Determine the toxicity of this regimen in these patients.

• Evaluate the therapeutic activity of this regimen in these patients.

• Evaluate the pharmacokinetic interaction of this regimen.

• Correlate clinical (toxicity and/or tumor response or activity) effects with pharmacologic (pharmacokinetic/pharmacodynamic) parameters and/or biologic (correlative laboratory) results.

OUTLINE: This is a multicenter, dose-escalation, phase I study followed by a phase II study.

• Phase I (closed to accrual as of 2/10/2009): Patients receive oral sorafenib tosylate and oral everolimus on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of sorafenib tosylate and everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 out of at most 6 patients experience a Dose Limiting Toxicity (DLT).

• Phase II: Patients receive oral sorafenib tosylate twice daily and oral everolimus once daily at the MTD determined in phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow are collected periodically during the study and analyzed by flow cytometry, immunohistochemistry, and enzyme-linked immunosorbent assay. Patients enrolled in phase I also undergo blood sample collection on days 8 and 15 during course 1 and on day 1 of each subsequent course for pharmacokinetic studies.

After completion of study treatment, patients are followed every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 103 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of the Raf Kinase/VEGFR Inhibitor Sorafenib in Combination With the mTOR Inhibitor RAD001 (Everolimus) in Patients With Relapsed Non-Hodgkin Lymphoma, Hodgkin Lymphoma, or Multiple Myeloma
• Actual Study Start Date: Aug 29, 2007
• Actual Primary Completion Date: Nov 5, 2011
• Actual Study Completion Date: Aug 8, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Multiple Myeloma Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day; Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day; Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day; Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day; Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;	Drug: RAD001; Phase I: Dose level 0: RAD001 5mg every other day; Dose level 1: RAD001 5mg every day; Dose level 2: RAD001 5mg every day; Dose level 3: RAD001 10mg every day; Phase II: RAD001 5mg every day; Other Names: Everolimus ; Drug: Sorafenib; Phase I: Dose level 0: Sorafenib 200 mg twice daily; Dose level 1: Sorafenib 200 mg twice daily; Dose level 2: Sorafenib 400 mg twice daily; Dose level 3: Sorafenib 400 mg twice daily; Phase II: Sorafenib 200 mg twice daily; Other Names: sorafenib tosylate
Experimental: Lymphoma Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day; Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day; Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day; Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day; Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;	Drug: RAD001; Phase I: Dose level 0: RAD001 5mg every other day; Dose level 1: RAD001 5mg every day; Dose level 2: RAD001 5mg every day; Dose level 3: RAD001 10mg every day; Phase II: RAD001 5mg every day; Other Names: Everolimus ; Drug: Sorafenib; Phase I: Dose level 0: Sorafenib 200 mg twice daily; Dose level 1: Sorafenib 200 mg twice daily; Dose level 2: Sorafenib 400 mg twice daily; Dose level 3: Sorafenib 400 mg twice daily; Phase II: Sorafenib 200 mg twice daily; Other Names: sorafenib tosylate

Outcome Measures

Primary Outcome Measures

1. Number of Participants Reporting a Dose Limiting Toxicity (DLT) [First cycle (28 days) of study treatment]

   The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). Dose-limiting toxicity (DLT) is defined as an adverse event attributed (definitely, probably, or possibly) in first cycle to the study treatment and meeting the following criteria: Grade 4 infection Grade 4 ANC or PLT Grade 3 or higher non-hematologic adverse event. NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 will be used to assess adverse events. For this endpoint, the number of patients reporting a DLT event are tabulated.

2. Proportion of Confirmed Tumor Responses [Up to 12 cycles of treatment]

   A confirmed response is defined to be a CR or PR noted as the objective status for eligible patients during cycles 1-12. Complete Response (CR): Multiple Myeloma (MM): Negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, and normalization of free light chain (FLC) ratio. Lymphoma: Disappearance of all clinical and radiographic evidence of disease, all lymph nodes of normal size (1.5 cm or less), no splenomegaly. Partial Response (PR): MM: 50% reduction of serum or urine M-protein or to less than 200mg/day, a 50% reduction in the difference between involved and uninvolved FLC, and 50% reduction in the size of soft tissue plasmacytoma. Lymphoma: 50% or greater reduction in sum of the products of the dimension for nodal masses; no increase in liver, spleen or node size; no new sites of disease; and a 50% decrease in lymphocyte count if followed at baseline.

Secondary Outcome Measures

1. Survival Time [Up to 3 years from registration]

   Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.

2. Progression Free Survival [Up to 3 years from registration]

   Progression Free Survival is defined as the time from registration to the earliest date documentation of disease progression or death. The distribution of time to disease progression will be estimated using the method of Kaplan-Meier.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following:

• Multiple myeloma

• Non-Hodgkin's lymphoma

• Hodgkin's lymphoma

• Relapsed or refractory disease

• Measurable disease, as defined according to diagnosis as follows:

• Multiple myeloma, meeting 1 of the following criteria:

• Serum monoclonal protein ≥ 1.0 g/dL

• Urine monoclonal protein ≥ 200 mg by 24-hour electrophoresis

• Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio

• Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease)

• Lymphoma, meeting 1 of the following criteria:

• Measurable disease by CT scan or MRI or PET/CT scan, defined as ≥ 1 lesion that has a single diameter of ≥ 2 cm OR tumor cells in the blood ≥ 5 x10^9/L

• Skin lesions can be used if the area is ≥ 2 cm in ≥ 1 diameter and photographed with a ruler

• Lymphoplasmacytic lymphoma without measurable lymphadenopathy, meeting both of the following criteria:

• Bone marrow lymphoplasmacytosis with > 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy

• Quantitative IgM monoclonal protein > 1,000 mg/dL

• Not a candidate for known standard potentially curative therapy

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Life expectancy ≥ 12 weeks

• ANC ≥ 1,500/mm³

• Hemoglobin ≥ 9 g/dL

• Platelet count ≥ 75,000/mm³

• Bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct bilirubin normal

• AST ≤ 3 times ULN (5 times ULN if liver involvement)

• Creatinine ≤ 2.5 times ULN

• INR < 1.5 or activated PTT < 1.5 times ULN (no concurrent anticoagulants)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective barrier contraception during and for at least 2 weeks after completion of study treatment

• No uncontrolled infection

• No NYHA class III-IV congestive heart failure

• No unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months)

• No myocardial infarction within the past 6 months

• No uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg or diastolic BP > 90 mm Hg, despite optimal medical management

• No known HIV positivity

• No other active malignancy requiring treatment

• No inability to swallow

• No gastrointestinal (GI) function impairment or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection) or preclude use of oral medications

• No thrombolic or embolic events (e.g., cerebrovascular accident, including transient ischemic attacks) within the past 6 months

• No pulmonary hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks

• No severe or uncontrolled medical conditions or other conditions that would preclude study compliance

• No liver disease, such as cirrhosis, chronic hepatitis or chronic persistent hepatitis, or uncontrolled infections

• No serious nonhealing wound, ulcer, or bone fracture

• No evidence or history of serious bleeding diathesis or coagulopathy, such as hemophilia or von Willebrand's disease

• No significant traumatic injury within the past 4 weeks

• No known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus)

PRIOR CONCURRENT THERAPY:

• More than 3 weeks since prior myelosuppressive chemotherapy or biological therapy and recovered

• More than 4 weeks since prior major surgery or open biopsy

• Lymph node biopsy within past 4 weeks allowed

• Prior everolimus allowed

• No concurrent immunosuppressant therapy

• Concurrent stable chronic doses of steroids (≤ 20 mg of prednisone per day) for disorders other than lymphoma (i.e., rheumatoid arthritis, polymyalgia rheumatica, adrenal insufficiency, asthma) or for pruritus or fever associated with lymphoma allowed

• Concurrent corticosteroids at the lowest possible dose necessary to control symptoms in patients with CNS lymphoma allowed

• No concurrent CYP450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort)

• No other concurrent immunotherapy, radiotherapy, or chemotherapy

• No concurrent chronic oxygen therapy

• No concurrent warfarin or heparin

• No other concurrent investigational therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
2	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• University of Iowa

Investigators

• Principal Investigator: Thomas E. Witzig, MD, Mayo Clinic
• Principal Investigator: Shaji K. Kumar, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00474929
• Other Study ID Numbers: LS0689; 07-000710; LS0689
• First Posted: May 17, 2007
• Last Update Posted: Aug 20, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Mayo Clinic: recurrent adult Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; stage III multiple myeloma; refractory multiple myeloma; Waldenström macroglobulinemia; recurrent adult Burkitt lymphoma; recurrent adult diffuse large cell lymphoma; recurrent adult diffuse mixed cell lymphoma; recurrent adult diffuse small cleaved cell lymphoma; recurrent adult immunoblastic large cell lymphoma; recurrent adult lymphoblastic lymphoma; recurrent grade 1 follicular lymphoma; recurrent grade 2 follicular lymphoma; recurrent grade 3 follicular lymphoma; recurrent mantle cell lymphoma; recurrent marginal zone lymphoma; recurrent small lymphocytic lymphoma; cutaneous B-cell non-Hodgkin lymphoma; extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue; nodal marginal zone B-cell lymphoma; splenic marginal zone lymphoma; recurrent mycosis fungoides/Sezary syndrome; recurrent adult grade III lymphomatoid granulomatosis
• Additional relevant MeSH terms: Lymphoma; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Everolimus; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Phase I, Dose Level 0	Phase I, Dose Level 1	Phase I, Dose Level 2	Phase I, Dose Level 3	Phase II
Arm/Group Description	Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day	Phase I: Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day	Phase I: Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day	Phase I: Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day	Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;
Period Title: Overall Study
STARTED	6	6	7	7	77
COMPLETED	6	5	5	5	77
NOT COMPLETED	0	1	2	2	0

Baseline Characteristics

Arm/Group Title	Phase I, Dose Level 0	Phase I, Dose Level 1	Phase I, Dose Level 2	Phase I, Dose Level 3	Phase II	Total
Arm/Group Description	Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day;	Phase I: Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day	Phase I: Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day	Phase I: Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day	Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;	Total of all reporting groups
Overall Participants	6	5	5	5	77	98
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	43	63	56	61	61	61
Sex: Female, Male (Count of Participants)
Female	3 50%	1 20%	1 20%	1 20%	30 39%	36 36.7%
Male	3 50%	4 80%	4 80%	4 80%	47 61%	62 63.3%
Region of Enrollment (participants) [Number]
United States	6 100%	5 100%	5 100%	5 100%	77 100%	98 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Reporting a Dose Limiting Toxicity (DLT)
Description	The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients). Dose-limiting toxicity (DLT) is defined as an adverse event attributed (definitely, probably, or possibly) in first cycle to the study treatment and meeting the following criteria: Grade 4 infection Grade 4 ANC or PLT Grade 3 or higher non-hematologic adverse event. NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 will be used to assess adverse events. For this endpoint, the number of patients reporting a DLT event are tabulated.
Time Frame	First cycle (28 days) of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I, Dose Level 0	Phase I, Dose Level 1	Phase I, Dose Level 2	Phase I, Dose Level 3
Arm/Group Description	Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day	Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day	Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day	Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day
Measure Participants	6	5	5	5
Number [participants]	1 16.7%	0 0%	1 20%	2 40%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase I, Dose Level 0, Phase I, Dose Level 1, Phase I, Dose Level 2, Phase I, Dose Level 3
	Comments	The Maximum Tolerated Dose (MTD) is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients (at least 2 of a maximum of 6 new patients).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Maximum Tolerated Dose (MTD) Level
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Dose Level 1 was chosen as the MTD due to PI concerns about adverse events and frequent dose reductions seen on later cycles at dose level 2. For the best interest of the patients, dose level 1 was chosen as the MTD and the dose level for Phase II.

2. Primary Outcome

Title	Proportion of Confirmed Tumor Responses
Description	A confirmed response is defined to be a CR or PR noted as the objective status for eligible patients during cycles 1-12. Complete Response (CR): Multiple Myeloma (MM): Negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, and normalization of free light chain (FLC) ratio. Lymphoma: Disappearance of all clinical and radiographic evidence of disease, all lymph nodes of normal size (1.5 cm or less), no splenomegaly. Partial Response (PR): MM: 50% reduction of serum or urine M-protein or to less than 200mg/day, a 50% reduction in the difference between involved and uninvolved FLC, and 50% reduction in the size of soft tissue plasmacytoma. Lymphoma: 50% or greater reduction in sum of the products of the dimension for nodal masses; no increase in liver, spleen or node size; no new sites of disease; and a 50% decrease in lymphocyte count if followed at baseline.
Time Frame	Up to 12 cycles of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib 200 mg Twice Daily, RAD001 5mg Every Day
Arm/Group Description	This endpoint was analyzed using all patients treated at the MTD (Dose Level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day). Due to concerns about adverse events and frequent dose reductions seen on later cycles at dose level 2, the PI felt it was in the best interest of the patients to choose dose level 1 as the MTD and the dose level for Phase II. Therefore, the analysis of the Phase II endpoint includes the eligible Phase I participants treated at Dose Level 1 (N=5) and it includes all participants treated in Phase II (N=77).
Measure Participants	82
Complete Response (CR)	8.5 141.7%
Partial Response (PR)	15.9 265%

3. Secondary Outcome

Title	Survival Time
Description	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time Frame	Up to 3 years from registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib 200 mg Twice Daily, RAD001 5mg Every Day
Arm/Group Description	This endpoint was analyzed using all patients treated at the MTD (Dose Level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day). This includes the eligible Phase I participants treated at Dose Level 1 (N=5) and it includes all participants treated in Phase II (N=77).
Measure Participants	82
Median (95% Confidence Interval) [months]	13.5

4. Secondary Outcome

Title	Progression Free Survival
Description	Progression Free Survival is defined as the time from registration to the earliest date documentation of disease progression or death. The distribution of time to disease progression will be estimated using the method of Kaplan-Meier.
Time Frame	Up to 3 years from registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib 200 mg Twice Daily, RAD001 5mg Every Day
Arm/Group Description	This endpoint was analyzed using all patients treated at the MTD (Dose Level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day). This includes the eligible Phase I participants treated at Dose Level 1 (N=5) and it includes all participants treated in Phase II (N=77).
Measure Participants	82
Median (95% Confidence Interval) [months]	4.6

Adverse Events

Time Frame	The adverse events reported here occurred during treatment. The maximum treatment length was 27, 28-day cycles.
Adverse Event Reporting Description	Adverse events were collected at the end of each cycle.
Arm/Group Title	Phase I, Dose Level 0		Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase II
Arm/Group Description	Phase I: Dose level 0: Sorafenib 200 mg twice daily, RAD001 5mg every other day		Phase I: Dose level 1: Sorafenib 200 mg twice daily, RAD001 5mg every day		Phase I: Dose level 2: Sorafenib 400 mg twice daily, RAD001 5mg every day		Phase I: Dose level 3: Sorafenib 400 mg twice daily, RAD001 10mg every day		Phase II: Sorafenib 200 mg twice daily, RAD001 5mg every day;
All Cause Mortality
	Phase I, Dose Level 0		Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase II
	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
	Phase I, Dose Level 0		Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		1/5 (20%)		2/5 (40%)		1/5 (20%)		22/77 (28.6%)
Blood and lymphatic system disorders
Hemoglobin decreased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/77 (3.9%)	3
Cardiac disorders
Cardiac valve disease	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Sinus bradycardia	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Gastrointestinal disorders
Diarrhea	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Ear, nose and throat examination abnormal	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Nausea	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
General disorders
Death	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Disease progression	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Fatigue	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Fever	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Sudden death	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Immune system disorders
Hypersensitivity	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Infections and infestations
Infectious colitis	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Sepsis	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Investigations
Bilirubin increased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Leukocyte count decreased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Lymphocyte count decreased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Neutrophil count decreased	1/6 (16.7%)	1	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	2/77 (2.6%)	4
Platelet count decreased	1/6 (16.7%)	2	1/5 (20%)	1	1/5 (20%)	1	1/5 (20%)	2	2/77 (2.6%)	2
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Musculoskeletal and connective tissue disorders
Myalgia	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Nervous system disorders
Ataxia	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Skin and subcutaneous tissue disorders
Hand-and-foot syndrome	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Rash desquamating	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	2/77 (2.6%)	2
Urticaria	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Vascular disorders
Hypotension	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Thrombosis	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase I, Dose Level 0		Phase I, Dose Level 1		Phase I, Dose Level 2		Phase I, Dose Level 3		Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		5/5 (100%)		5/5 (100%)		5/5 (100%)		76/77 (98.7%)
Blood and lymphatic system disorders
Hemoglobin decreased	3/6 (50%)	13	2/5 (40%)	2	4/5 (80%)	12	3/5 (60%)	15	31/77 (40.3%)	63
Hemolysis	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	3
Thrombotic microangiopathy	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Cardiac disorders
Atrial fibrillation	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Cardiac disorder	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Ear and labyrinth disorders
Hearing loss	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	0/77 (0%)	0
Hyperthyroidism	1/6 (16.7%)	2	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/77 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/77 (5.2%)	4
Constipation	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Diarrhea	3/6 (50%)	12	2/5 (40%)	8	3/5 (60%)	10	5/5 (100%)	20	53/77 (68.8%)	266
Dry mouth	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Ear, nose and throat examination abnormal	1/6 (16.7%)	1	0/5 (0%)	0	1/5 (20%)	2	2/5 (40%)	3	16/77 (20.8%)	35
Enteritis	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Gingival pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Hemorrhoids	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Nausea	5/6 (83.3%)	7	2/5 (40%)	4	3/5 (60%)	6	4/5 (80%)	5	35/77 (45.5%)	90
Oral pain	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Stomach pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Toothache	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Vomiting	3/6 (50%)	7	1/5 (20%)	2	1/5 (20%)	3	4/5 (80%)	6	20/77 (26%)	27
General disorders
Chills	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Death	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/5 (0%)	0	0/77 (0%)	0
Edema limbs	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	3/77 (3.9%)	6
Fatigue	6/6 (100%)	33	4/5 (80%)	7	4/5 (80%)	19	4/5 (80%)	26	67/77 (87%)	357
Fever	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/5 (20%)	1	1/77 (1.3%)	3
Immune system disorders
Hypersensitivity	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Infections and infestations
Bronchitis	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Colitis, infectious (e.g., Clostridium difficile)	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Gingival infection	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Kidney infection	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Otitis externa	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Pneumonia	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	4/77 (5.2%)	7
Sepsis	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Sinusitis	1/6 (16.7%)	3	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Skin infection	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/77 (5.2%)	5
Soft tissue infection	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Tooth infection	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Upper respiratory infection	1/6 (16.7%)	1	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/77 (1.3%)	1
Urinary tract infection	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Injury, poisoning and procedural complications
Intraoperative respiratory injury - Nasal cavity	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Investigations
Alanine aminotransferase increased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/77 (5.2%)	7
Alkaline phosphatase increased	1/6 (16.7%)	3	1/5 (20%)	3	1/5 (20%)	1	0/5 (0%)	0	4/77 (5.2%)	12
Aspartate aminotransferase increased	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/5 (0%)	0	3/77 (3.9%)	3
Bilirubin increased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	3
Creatine phosphokinase increased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	3
Creatinine increased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	4/77 (5.2%)	4
Laboratory test abnormal	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Leukocyte count decreased	2/6 (33.3%)	6	1/5 (20%)	1	1/5 (20%)	1	5/5 (100%)	18	23/77 (29.9%)	50
Lymphocyte count decreased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/5 (40%)	7	6/77 (7.8%)	23
Neutrophil count decreased	2/6 (33.3%)	2	2/5 (40%)	5	1/5 (20%)	1	5/5 (100%)	20	19/77 (24.7%)	34
Platelet count decreased	3/6 (50%)	8	2/5 (40%)	4	2/5 (40%)	5	3/5 (60%)	22	32/77 (41.6%)	99
Serum cholesterol increased	1/6 (16.7%)	3	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	2
Weight loss	1/6 (16.7%)	1	1/5 (20%)	1	1/5 (20%)	4	0/5 (0%)	0	2/77 (2.6%)	6
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	2/5 (40%)	2	1/5 (20%)	1	2/5 (40%)	3	6/77 (7.8%)	8
Blood glucose increased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/77 (5.2%)	8
Dehydration	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Serum calcium decreased	0/6 (0%)	0	1/5 (20%)	2	2/5 (40%)	2	0/5 (0%)	0	1/77 (1.3%)	2
Serum phosphate decreased	2/6 (33.3%)	7	1/5 (20%)	2	3/5 (60%)	8	2/5 (40%)	2	10/77 (13%)	27
Serum potassium decreased	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/77 (1.3%)	3
Serum sodium decreased	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Serum triglycerides increased	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	5/77 (6.5%)	8
Musculoskeletal and connective tissue disorders
Back pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Chest wall pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Joint pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	3
Myalgia	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Pain in extremity	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/6 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/5 (0%)	0	0/77 (0%)	0
Nervous system disorders
Dizziness	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Headache	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Ischemia cerebrovascular	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Peripheral motor neuropathy	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	2
Peripheral sensory neuropathy	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	8
Taste alteration	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Psychiatric disorders
Depression	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Insomnia	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Renal and urinary disorders
Bladder obstruction	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Ureteric obstruction	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	0/77 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/77 (0%)	0
Cough	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	3/77 (3.9%)	4
Dyspnea	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	4
Hemorrhage nasal	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Nasal congestion	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	3	0/77 (0%)	0
Pharyngolaryngeal pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Pneumonitis	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/77 (3.9%)	4
Pulmonary hemorrhage	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Respiratory disorder	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/77 (0%)	0
Voice alteration	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Skin and subcutaneous tissue disorders
Alopecia	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/77 (1.3%)	1
Dry skin	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Erythema multiforme	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Hand-and-foot syndrome	1/6 (16.7%)	1	1/5 (20%)	1	2/5 (40%)	6	2/5 (40%)	13	16/77 (20.8%)	78
Pruritus	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	2
Rash desquamating	4/6 (66.7%)	10	0/5 (0%)	0	3/5 (60%)	4	5/5 (100%)	8	42/77 (54.5%)	105
Scalp pain	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/77 (2.6%)	3
Skin disorder	0/6 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/77 (1.3%)	1
Vascular disorders
Hypertension	1/6 (16.7%)	7	1/5 (20%)	1	1/5 (20%)	3	1/5 (20%)	4	18/77 (23.4%)	76
Thrombosis	0/6 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	0/5 (0%)	0	1/77 (1.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.