Linsitinib or Topotecan Hydrochloride in Treating Patients With Relapsed Small Cell Lung Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01533181
• Collaborator: (none)
• Enrollment: 44
• Locations: 11
• Arms: 2
• Duration (Months): 33
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate how OSI-906 compares to Topotecan in trying to slow down the growth and/or progression of the tumors of participants with relapsed or recurrent Small Cell Lung Cancer.

This study also plans to find out what effects, good or bad (side effects), OSI-906 has on participants and or Small Cell Lung Cancer. The study will also investigate if some proteins measured in the blood or tumor and some imaging features obtained from computed tomography (CT) scans can help predict whether OSI-906 or topotecan will be effective against Small Cell Lung Cancer.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Small Cell Lung Carcinoma	Other: Laboratory Biomarker Analysis; Drug: Linsitinib; Other: Pharmacological Study; Drug: Topotecan Hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To compare the progression-free survival (PFS) of single-agent OSI-906 (linsitinib) to that of single-agent topotecan (topotecan hydrochloride) in patients with relapsed small cell lung cancer (SCLC).

SECONDARY OBJECTIVES:

1. To evaluate the response rate (RR), disease-control rate (DCR) and overall survival (OS) of single-agent OSI-906 in patients with relapsed SCLC.

2. To describe the toxicity profile of single-agent OSI-906 in this population.

TERTIARY OBJECTIVES:

1. To evaluate potential predictive biomarkers of OSI-906 sensitivity. II. To determine whether the baseline insulin-like growth factor (IGF)-1, IGF-binding proteins (BPs), or angiogenic markers (vascular endothelial growth factor [VEGF] and interleukin [IL]-8) plasma levels or their pre- and post-treatment plasma level changes, significantly differ between progressor and non-progressor patients and correlate them with survival.

2. To assess whether the baseline protein kinase B (AKT) and/or mitogen-activated protein kinase 1 (ERK) phosphorylation or the extent of inhibition of AKT and/or ERK phosphorylation in peripheral blood mononuclear cells (PBMCs) significantly differs between progressors and non-progressors and to correlate them with survival.

3. To determine whether the subcellular localization of IGF-1R, IGF-BPs, and/or the phosphorylation of IGF-1R throughout the cell by AQUA (automated quantitative immunofluorescence) significantly differs between progressors and non-progressors and correlate them with survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive linsitinib orally (PO) twice daily (BID) on days 1-21.

ARM II: Patients receive topotecan hydrochloride intravenously (IV) over 30 minutes or PO once daily (QD) on days 1-5. Patients may crossover to Arm I at the time of progressive disease.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks and then every 6 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of Single Agent OSI-906, an Oral, Small Molecule, Tyrosine Kinase Inhibitor (TKI) of the Insulin Growth Factor-1 Receptor (IGF-1R) Versus Topotecan for the Treatment of Patients With Relapsed Small Cell Lung Cancer (SCLC)
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I: OS-906 (linsitinib) OS-906 daily, continuously, every 3 weeks.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Linsitinib; 150 mg given orally (PO) twice a day (BID); Other Names: IGF-1R inhibitor OSI-906 OSI-906 OSI-906AA ; Other: Pharmacological Study; Correlative studies
Active Comparator: Arm II (topotecan hydrochloride) Patients receive topotecan hydrochloride IV over 30 minutes or PO QD on days 1-5. Patients may crossover to Arm I at the time of progressive disease.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Topotecan Hydrochloride; 1.5 mg/m^2 intravenously (IV) or 2.3 mg/m^2 orally (PO); Other Names: Hycamptamine Hycamtin SKF S-104864-A Topotecan HCl topotecan hydrochloride (oral)

Outcome Measures

Primary Outcome Measures

1. Median Progression Free Survival (PFS) [Up to 6 months]

   PFS: Time from randomization to time of disease progression or death. PFS summarized with the Kaplan-Meier (K-M) method by two arms (experimental versus control). Confidence intervals for the median PFS and PFS rates at different time points to be constructed when appropriate.

Secondary Outcome Measures

1. Disease Control Rate (DCR) [Up to 2 years]

   DCR: Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) + Progressive Disease (PD). DCR summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm.

2. Incidence of Serious Adverse Events (SAEs) Possibly/Probably Definitely Related to Study Drugs [1 year, 6 months]

   Participants with Grade 3 and 4 toxicities, possibly/probably/definitely related to study drugs. Number of Participants is per Event Category. Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

3. Overall Survival (OS) [Up to 2 years]

   OS: Time from study enrollment to death from any cause. OS summarized similarly to PFS utilizing the K-M method.

Other Outcome Measures

1. Changes in Biomarker Expression [Baseline to up to day 1 of course 3]

   To be assessed by the Wilcoxon rank sum test.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed SCLC

• Patients must have measurable disease; at least one lesion that can be accurately measured is required

• Patients must have progression of disease after receiving ONLY 1 previous platinum-containing regimen; prior treatment with biological response modifiers or targeted agents will NOT count towards this requirement; previous topotecan or any type of pharmacologic IGF-1R inhibition are NOT allowed

• Life expectancy of greater than 6 weeks

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2; (Karnofsky >= 60%)

• Leukocytes (white blood cell [WBC]) >= 3,000/mcL OR

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin within normal institutional limits (NIL)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 times institutional upper limit of normal (ULN) without demonstrable liver metastases OR < 5.0 times ULN with liver metastases present

• Serum creatinine within NIL OR measured/calculated creatinine clearance (CrCl) >= 60 mL/min/1.73 m^2 for patients with creatinine levels above NIL

• Fasting blood glucose < 160 mg/dL at baseline

• Patients on oral antihyperglycemic therapies may be enrolled provided they have been taking a stable dose of these medications for >= 2 weeks at the time of randomization

• Prior radiation is permitted IF the site(s) of measurable disease has progressed since prior irradiation and radiation is completed at least 2 weeks before initiation of drug treatment (stereotactic radiotherapy excluded)

• Patients with central nervous system (CNS) metastases are ELIGIBLE, provided that prior to drug treatment, the metastases have been treated, remain clinically or radiographically stable and the patient has no significant neurologic symptoms

• Patients must NOT have prior malignancy EXCEPT for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for >= 3 years

• Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; WOCBP must provide a negative pregnancy test (serum or urine) within 14 days prior to registration

• Available archival tumor tissue is NOT mandatory for enrollment (will be requested)

• Patients must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients who are receiving any other investigational agents

• Patients with CNS metastases are NOT EXCLUDED, provided that prior to drug treatment, the metastases have been treated, remain radiographically stable and the patient has no significant neurologic symptoms

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to OSI-906 or other agents used in the study (topotecan)

• While cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) inhibitors/inducers are not specifically excluded, investigators should be aware that the metabolism and consequently overall pharmacokinetics (PKs) of OSI-906 (OSI-906 exposure) could be altered by concomitant use of these drugs (inhibitors, inducers and/or other substrates of CYP1A2); exception: potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited; while cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) substrates are not specifically excluded, investigators should be aware that levels of drugs metabolized by CYP2C9 may be increased by the concomitant administration of OSI-906; caution should be used when administering CYP2C9 substrates to study patients

• The concomitant use of p-glycoprotein inhibitors with topotecan capsules is not allowed

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, significant cardiac disease (i.e., symptomatic congestive heart failure, unstable angina pectoris, symptomatic or life-threatening cardiac arrhythmia), or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant or breast-feeding women are excluded from this study

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Patients in the following scenarios are excluded:

• Corrected QT (QTc) interval > 450 msec at baseline

• Concomitant drugs that prolong the QTc interval

• Use of drugs that have a known risk of causing Torsades de Pointes (TdP) within 14 days prior to randomization

• Fasting blood glucose >= 160 mg/dL at baseline; these patients can initiate allowed oral antihyperglycemic therapies and be retested or rescreened 2 weeks later to meet baseline fasting blood glucose criteria

• Concomitant use of insulin or insulinotropic medications

• Patients with cirrhosis of the liver are excluded from this study

• Archival tumor tissue is NOT mandatory for enrollment, but will be requested

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Emory University/Winship Cancer Institute	Atlanta	Georgia	United States	30322
4	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
5	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital	Baltimore	Maryland	United States	21231
6	Billings Clinic Cancer Center	Billings	Montana	United States	59107
7	Case Western Reserve University	Cleveland	Ohio	United States	44106
8	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
9	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
10	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792
11	Johns Hopkins Singapore	Singapore		Singapore	308433

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Alberto Chiappori, Moffitt Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01533181
• Other Study ID Numbers: NCI-2012-00245; NCI-2012-00245; CDR0000724806; MCC-16628; MCC 16628; 8873; N01CM00070; N01CM00099; N01CM00100; P30CA076292; NCT01387386
• First Posted: Feb 15, 2012
• Last Update Posted: Jan 14, 2016
• Last Verified: Aug 1, 2015

• Additional relevant MeSH terms: Small Cell Lung Carcinoma; Topotecan

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at Moffitt Cancer Center and nine other institutions in the United States from July 3, 2012 through November 1, 2013.

Arm/Group Title	Arm A: Topotecan	Arm B: OS-906
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.	OS-906 (linsitinib) daily, continuously, every 3 weeks.
Period Title: Overall Study
STARTED	15	29
COMPLETED	14	28
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Arm A: Topotecan	Arm B: OS-906	Total
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.	OS-906 (linsitinib) daily, continuously, every 3 weeks.	Total of all reporting groups
Overall Participants	15	29	44
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	9 60%	17 58.6%	26 59.1%
>=65 years	6 40%	12 41.4%	18 40.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	62	64
Sex: Female, Male (Count of Participants)
Female	8 53.3%	17 58.6%	25 56.8%
Male	7 46.7%	12 41.4%	19 43.2%
Region of Enrollment (participants) [Number]
United States	15 100%	29 100%	44 100%

Outcome Measures

1. Primary Outcome

Title	Median Progression Free Survival (PFS)
Description	PFS: Time from randomization to time of disease progression or death. PFS summarized with the Kaplan-Meier (K-M) method by two arms (experimental versus control). Confidence intervals for the median PFS and PFS rates at different time points to be constructed when appropriate.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

All participants who received treatment

Arm/Group Title	Arm A: Topotecan	Arm B: OS-906
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.	OS-906 (linsitinib) daily, continuously, every 3 weeks.
Measure Participants	14	28
Median (95% Confidence Interval) [months]	3	1.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Topotecan, Arm B: OS-906
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Kaplan-Meier
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.9
	Confidence Interval	(2-Sided) 95%; 1.9 to 8.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR: Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) + Progressive Disease (PD). DCR summarized using both point estimates and exact confidence intervals based on the binomial distribution by arm.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All evaluable participants at time of analysis

Arm/Group Title	Arm A: Topotecan	Arm B: OS-906
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.	OS-906 (linsitinib) daily, continuously, every 3 weeks.
Measure Participants	12	25
Complete Response	0 0%	0 0%
Partial Response	2 13.3%	0 0%
Stable Disease	4 26.7%	1 3.4%
Progressive Disease	6 40%	24 82.8%
Disease Control Rate	6 40%	1 3.4%

3. Secondary Outcome

Title	Incidence of Serious Adverse Events (SAEs) Possibly/Probably Definitely Related to Study Drugs
Description	Participants with Grade 3 and 4 toxicities, possibly/probably/definitely related to study drugs. Number of Participants is per Event Category. Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Time Frame	1 year, 6 months

Outcome Measure Data

Analysis Population Description

All participants who received treatment

Arm/Group Title	Arm A: Topotecan	Arm B: OS-906
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.	OS-906 (linsitinib) daily, continuously, every 3 weeks.
Measure Participants	14	28
Anemia	1 6.7%	1 3.4%
Blood and lymphatic system disorders - Other	2 13.3%	0 0%
Thrombotic thrombocytopenic purpura	1 6.7%	0 0%
Diarrhea	1 6.7%	0 0%
Esophagitis	1 6.7%	0 0%
Pancreatitis	1 6.7%	0 0%
Fatigue	1 6.7%	3 10.3%
Alanine aminotransferase increased	0 0%	2 6.9%
Investigations - Other	1 6.7%	0 0%
Lymphocyte count decreased	2 13.3%	3 10.3%
Neutrophil count decreased	4 26.7%	0 0%
Platelet count decreased	4 26.7%	2 6.9%
White blood cell decreased	4 26.7%	0 0%
Anorexia	0 0%	1 3.4%
Dehydration	2 13.3%	0 0%
Hyperglycemia	0 0%	1 3.4%
Hypokalemia	1 6.7%	0 0%
Hyponatremia	0 0%	1 3.4%
Headache	0 0%	1 3.4%
Hypoxia	0 0%	1 3.4%
Thromboembolic event	1 6.7%	0 0%

4. Secondary Outcome

Title	Overall Survival (OS)
Description	OS: Time from study enrollment to death from any cause. OS summarized similarly to PFS utilizing the K-M method.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All participants who received treatment

Arm/Group Title	Arm A: Topotecan	Arm B: OS-906
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.	OS-906 (linsitinib) daily, continuously, every 3 weeks.
Measure Participants	14	28
Median (95% Confidence Interval) [months]	5.3	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Topotecan, Arm B: OS-906
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Kaplan-Meier
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; 0.6 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Changes in Biomarker Expression
Description	To be assessed by the Wilcoxon rank sum test.
Time Frame	Baseline to up to day 1 of course 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year, 6 months
Adverse Event Reporting Description	Adverse Events are reported for all participants who received treatment, regardless of causality. Grades 3, 4 and 5 are noted on the appropriate reported SAEs. Note: Causality for SAEs is addressed in the Secondary Outcome Measure area.
Arm/Group Title	Arm A: Topotocan		Arm B: OS-906
Arm/Group Description	Participants receive topotecan hydrochloride IV over 30 minutes or orally (PO) daily (QD) on days 1-5. Patients may crossover to Arm B at the time of progressive disease.		OS-906 (linsitinib) daily, continuously, every 3 weeks.
All Cause Mortality
	Arm A: Topotocan		Arm B: OS-906
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: Topotocan		Arm B: OS-906
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/14 (50%)		18/28 (64.3%)
Blood and lymphatic system disorders
Anemia	2/14 (14.3%)	2	0/28 (0%)	0
Blood and lymphatic system disorders - Other, Pancytopenia	1/14 (7.1%)	1	0/28 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/14 (0%)	0	1/28 (3.6%)	1
Diarrhea	1/14 (7.1%)	1	0/28 (0%)	0
Esophagitis	1/14 (7.1%)	1	0/28 (0%)	0
Nausea	1/14 (7.1%)	1	1/28 (3.6%)	1
Pancreatitis	1/14 (7.1%)	1	0/28 (0%)	0
Vomiting	1/14 (7.1%)	1	0/28 (0%)	0
General disorders
Death NOS	7/14 (50%)	7	12/28 (42.9%)	12
Fever	1/14 (7.1%)	1	0/28 (0%)	0
Non-cardiac chest pain	0/14 (0%)	0	1/28 (3.6%)	1
Pain	0/14 (0%)	0	1/28 (3.6%)	1
Infections and infestations
Enterocolitis infectious	1/14 (7.1%)	1	0/28 (0%)	0
Infections and infestations - Other, Possible pneumonia per x-ray	1/14 (7.1%)	1	0/28 (0%)	0
Lung infection	0/14 (0%)	0	3/28 (10.7%)	4
Urinary tract infection	0/14 (0%)	0	1/28 (3.6%)	1
Injury, poisoning and procedural complications
Fracture	1/14 (7.1%)	1	1/28 (3.6%)	1
Investigations
Alanine aminotransferase increased	0/14 (0%)	0	1/28 (3.6%)	1
Aspartate aminotransferase increased	0/14 (0%)	0	1/28 (3.6%)	1
Blood bilirubin increase	0/14 (0%)	0	1/28 (3.6%)	1
Lymphocyte count decreased	0/14 (0%)	0	1/28 (3.6%)	1
Neutrophil count decreased	1/14 (7.1%)	1	0/28 (0%)	0
Platelet count decreased	0/14 (0%)	0	1/28 (3.6%)	1
White blood cell decreased	2/14 (14.3%)	2	0/28 (0%)	0
Metabolism and nutrition disorders
Dehydration	2/14 (14.3%)	2	2/28 (7.1%)	2
Hyperglycemia	0/14 (0%)	0	2/28 (7.1%)	2
Hypokalemia	1/14 (7.1%)	1	0/28 (0%)	0
Hyponatremia	1/14 (7.1%)	1	0/28 (0%)	0
Hyponatremia	1/14 (7.1%)	1	1/28 (3.6%)	1
Musculoskeletal and connective tissue disorders
Bone pain	0/14 (0%)	0	1/28 (3.6%)	1
Muscle weakness left-sided	0/14 (0%)	0	1/28 (3.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other, Progressive disease	0/14 (0%)	0	3/28 (10.7%)	3
Neoplasms benign, malignant and unspecified - Other, Death	0/14 (0%)	0	6/28 (21.4%)	6
Tumor pain	0/14 (0%)	0	1/28 (3.6%)	1
Nervous system disorders
Headache	0/14 (0%)	0	1/28 (3.6%)	1
Intracranial hemorrhage	1/14 (7.1%)	1	0/28 (0%)	0
Lethargy	0/14 (0%)	0	1/28 (3.6%)	1
Psychiatric disorders
Confusion	1/14 (7.1%)	1	1/28 (3.6%)	1
Renal and urinary disorders
Acute kidney injury	0/14 (0%)	0	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/14 (7.1%)	1	0/28 (0%)	0
Dyspnea	0/14 (0%)	0	3/28 (10.7%)	6
Hypoxia	0/14 (0%)	0	2/28 (7.1%)	2
Respiratory failure	0/14 (0%)	0	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders - Other, COPD	0/14 (0%)	0	1/28 (3.6%)	1
Vascular disorders
Hypotension	1/14 (7.1%)	1	0/28 (0%)	0
Superior vena cava syndrome - Death	0/14 (0%)	0	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	Arm A: Topotocan		Arm B: OS-906
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/14 (85.7%)		28/28 (100%)
Blood and lymphatic system disorders
Anemia	11/14 (78.6%)	25	7/28 (25%)	12
Blood and lymphatic system disorders - Other	2/14 (14.3%)	2	2/28 (7.1%)	2
Thrombotic thrombocytopenic purpura	1/14 (7.1%)	1	0/28 (0%)	0
Cardiac disorders
Sinus tachycardia	1/14 (7.1%)	1	1/28 (3.6%)	1
Atrial fibrillation	0/14 (0%)	0	1/28 (3.6%)	1
Ear and labyrinth disorders
Ear pain	0/14 (0%)	0	1/28 (3.6%)	2
Tinnitus	1/14 (7.1%)	2	0/28 (0%)	0
Eye disorders
Eyelid function disorder	0/14 (0%)	0	1/28 (3.6%)	1
Watering eyes	0/14 (0%)	0	1/28 (3.6%)	1
Gastrointestinal disorders
Nausea	6/14 (42.9%)	7	13/28 (46.4%)	15
Vomiting	6/14 (42.9%)	8	8/28 (28.6%)	10
Constipation	5/14 (35.7%)	5	8/28 (28.6%)	9
Diarrhea	3/14 (21.4%)	4	6/28 (21.4%)	8
Dyspepsia	1/14 (7.1%)	1	0/28 (0%)	0
Gastrointestinal disorders - Other	0/14 (0%)	0	4/28 (14.3%)	4
Abdominal pain	0/14 (0%)	0	3/28 (10.7%)	3
Mucositis oral	2/14 (14.3%)	2	1/28 (3.6%)	1
Dysphagia	0/14 (0%)	0	2/28 (7.1%)	2
Gastroesophageal reflux disease	1/14 (7.1%)	1	1/28 (3.6%)	1
Bloating	0/14 (0%)	0	1/28 (3.6%)	1
Fecal incontinence	0/14 (0%)	0	1/28 (3.6%)	1
Gastritis	1/14 (7.1%)	1	0/28 (0%)	0
Oral hemorrhage	1/14 (7.1%)	1	0/28 (0%)	0
Oral pain	0/14 (0%)	0	1/28 (3.6%)	1
Pancreatitis	1/14 (7.1%)	1	0/28 (0%)	0
Stomach pain	1/14 (7.1%)	2	0/28 (0%)	0
General disorders
Fatigue	8/14 (57.1%)	11	16/28 (57.1%)	18
Pain	3/14 (21.4%)	3	6/28 (21.4%)	8
Chills	1/14 (7.1%)	1	2/28 (7.1%)	2
Fever	2/14 (14.3%)	2	0/28 (0%)	0
General Disorders - Other	1/14 (7.1%)	1	2/28 (7.1%)	2
Flu like symptoms	0/14 (0%)	0	2/28 (7.1%)	2
Malaise	1/14 (7.1%)	1	1/28 (3.6%)	1
Non-cardiac chest pain	0/14 (0%)	0	2/28 (7.1%)	2
Edema face	0/14 (0%)	0	1/28 (3.6%)	1
Edema limbs	0/14 (0%)	0	1/28 (3.6%)	1
Edema trunk	1/14 (7.1%)	1	0/28 (0%)	0
Facial pain	0/14 (0%)	0	1/28 (3.6%)	1
Gait disturbance	1/14 (7.1%)	1	0/28 (0%)	0
Immune system disorders
Allergic reaction	0/14 (0%)	0	1/28 (3.6%)	1
Infections and infestations
Infections and infestations - Other	0/14 (0%)	0	1/28 (3.6%)	1
Lung infection	0/14 (0%)	0	1/28 (3.6%)	1
Upper respiratory infection	1/14 (7.1%)	1	0/28 (0%)	0
Urinary tract infection	0/14 (0%)	0	1/28 (3.6%)	2
Vaginal infection	0/14 (0%)	0	1/28 (3.6%)	1
Injury, poisoning and procedural complications
Bruising	0/14 (0%)	0	1/28 (3.6%)	1
Fracture	0/14 (0%)	0	1/28 (3.6%)	1
Investigations
Aspartate aminotransferase increased	1/14 (7.1%)	1	8/28 (28.6%)	10
White blood cell decreased	7/14 (50%)	14	2/28 (7.1%)	5
Alanine aminotransferase increased	1/14 (7.1%)	1	7/28 (25%)	9
Lymphocyte count decreased	5/14 (35.7%)	15	5/28 (17.9%)	15
Platelet count decreased	4/14 (28.6%)	9	4/28 (14.3%)	7
Blood bilirubin increased	1/14 (7.1%)	1	6/28 (21.4%)	6
Weight loss	0/14 (0%)	0	6/28 (21.4%)	6
Alkaline phosphatase increased	0/14 (0%)	0	5/28 (17.9%)	6
Neutrophil count decreased	5/14 (35.7%)	8	0/28 (0%)	0
Creatinine increased	0/14 (0%)	0	4/28 (14.3%)	7
Electrocardiogram QT corrected interval prolonged	1/14 (7.1%)	1	1/28 (3.6%)	1
INR increased	1/14 (7.1%)	1	1/28 (3.6%)	1
Investigations - Other	2/14 (14.3%)	3	1/28 (3.6%)	1
Cardiac troponin I increased	1/14 (7.1%)	1	0/28 (0%)	0
CD4 lymphocytes decreased	0/14 (0%)	0	1/28 (3.6%)	1
Metabolism and nutrition disorders
Anorexia	7/14 (50%)	7	12/28 (42.9%)	13
Hyponatremia	2/14 (14.3%)	2	11/28 (39.3%)	19
Hyperglycemia	3/14 (21.4%)	3	8/28 (28.6%)	10
Hypoalbuminemia	4/14 (28.6%)	4	8/28 (28.6%)	14
Dehydration	4/14 (28.6%)	6	4/28 (14.3%)	4
Hypokalemia	2/14 (14.3%)	2	6/28 (21.4%)	9
Hypocalcemia	2/14 (14.3%)	2	5/28 (17.9%)	5
Hyperkalemia	1/14 (7.1%)	1	2/28 (7.1%)	2
Hypomagnesemia	1/14 (7.1%)	1	2/28 (7.1%)	4
Hypophosphatemia	0/14 (0%)	0	2/28 (7.1%)	2
Metabolism and nutrition disorders - Other	0/14 (0%)	0	2/28 (7.1%)	2
Alkalosis	0/14 (0%)	0	1/28 (3.6%)	1
Hypercalcemia	0/14 (0%)	0	1/28 (3.6%)	3
Hypernatremia	0/14 (0%)	0	1/28 (3.6%)	1
Hypoglycemia	0/14 (0%)	0	1/28 (3.6%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	2/14 (14.3%)	2	3/28 (10.7%)	7
Back pain	1/14 (7.1%)	1	3/28 (10.7%)	4
Generalized muscle weakness	1/14 (7.1%)	1	3/28 (10.7%)	4
Bone pain	1/14 (7.1%)	1	1/28 (3.6%)	1
Muscle weakness lower limb	0/14 (0%)	0	2/28 (7.1%)	2
Neck pain	1/14 (7.1%)	1	1/28 (3.6%)	1
Flank pain	0/14 (0%)	0	1/28 (3.6%)	1
Muscle weakness left-sided	0/14 (0%)	0	1/28 (3.6%)	1
Musculoskeletal and connective tissue disorder - Other	1/14 (7.1%)	1	0/28 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	1/14 (7.1%)	1	8/28 (28.6%)	8
Nervous system disorders
Dizziness	2/14 (14.3%)	4	3/28 (10.7%)	3
Headache	3/14 (21.4%)	5	2/28 (7.1%)	5
Peripheral sensory neuropathy	0/14 (0%)	0	3/28 (10.7%)	3
Lethargy	0/14 (0%)	0	1/28 (3.6%)	1
Amnesia	1/14 (7.1%)	1	0/28 (0%)	0
Dysarthria	0/14 (0%)	0	1/28 (3.6%)	3
Nervous system disorders - Other	1/14 (7.1%)	1	0/28 (0%)	0
Paresthesia	0/14 (0%)	0	1/28 (3.6%)	1
Phantom pain	0/14 (0%)	0	1/28 (3.6%)	1
Syncope	1/14 (7.1%)	1	0/28 (0%)	0
Psychiatric disorders
Confusion	2/14 (14.3%)	2	1/28 (3.6%)	1
Insomnia	0/14 (0%)	0	2/28 (7.1%)	2
Anxiety	1/14 (7.1%)	1	0/28 (0%)	0
Renal and urinary disorders
Urinary incontinence	0/14 (0%)	0	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/14 (21.4%)	3	8/28 (28.6%)	8
Cough	4/14 (28.6%)	4	6/28 (21.4%)	6
Epistaxis	2/14 (14.3%)	3	2/28 (7.1%)	2
Hypoxia	1/14 (7.1%)	1	3/28 (10.7%)	4
Pneumonitis	2/14 (14.3%)	2	2/28 (7.1%)	2
Pleural effusion	1/14 (7.1%)	1	2/28 (7.1%)	2
Productive cough	1/14 (7.1%)	1	1/28 (3.6%)	1
Sore throat	1/14 (7.1%)	1	1/28 (3.6%)	1
Bronchial obstruction	0/14 (0%)	0	1/28 (3.6%)	1
Bronchopulmonary hemorrhage	0/14 (0%)	0	1/28 (3.6%)	1
Hoarseness	1/14 (7.1%)	1	0/28 (0%)	0
Nasal congestion	1/14 (7.1%)	1	0/28 (0%)	0
Pleuritic pain	0/14 (0%)	0	1/28 (3.6%)	1
Postnasal drip	1/14 (7.1%)	1	0/28 (0%)	0
Pulmonary hypertension	0/14 (0%)	0	1/28 (3.6%)	1
Wheezing	0/14 (0%)	0	1/28 (3.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	2/14 (14.3%)	2	1/28 (3.6%)	1
Hyperhidrosis	0/14 (0%)	0	2/28 (7.1%)	2
Skin and subcutaneous tissue disorders - Other	1/14 (7.1%)	1	1/28 (3.6%)	1
Hypohidrosis	0/14 (0%)	0	1/28 (3.6%)	1
Pruritus	0/14 (0%)	0	1/28 (3.6%)	1
Rash maculo-papular	1/14 (7.1%)	1	0/28 (0%)	0
Skin hyperpigmentation	0/14 (0%)	0	1/28 (3.6%)	1
Skin ulceration	1/14 (7.1%)	1	0/28 (0%)	0
Vascular disorders
Hypotension	1/14 (7.1%)	1	4/28 (14.3%)	4
Hypertension	2/14 (14.3%)	3	1/28 (3.6%)	1
Thromboembolic event	1/14 (7.1%)	4	1/28 (3.6%)	1
Vascular disorders - Other	2/14 (14.3%)	2	0/28 (0%)	0
Flushing	1/14 (7.1%)	1	2/28 (7.1%)	2
Hot flashes	0/14 (0%)	0	1/28 (3.6%)	1
Superior vena cava syndrome	0/14 (0%)	0	1/28 (3.6%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.