Study Evaluating Safety And Tolerability, Solid Tumor

• Sponsor: Puma Biotechnology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00768469
• Collaborator: (none)
• Enrollment: 10
• Locations: 2
• Arms: 2
• Actual Duration (Months): 27
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is an open-label, phase 1 study of ascending multiple oral doses of HKI-272 in combination with paclitaxel.

Condition or Disease	Intervention/Treatment	Phase
Advanced Malignant Solid Tumors	Drug: Neratinib; Drug: Paclitaxel	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Study Of Neratinib (HKI-272) In Combination With Paclitaxel In Subjects With Solid Tumors
• Actual Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Jan 1, 2011
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nera 160 + Pac Neratinib 160 mg + Paclitaxel 80 mg/m^2	Drug: Neratinib; Administered orally, continuous, once daily.; Other Names: HKI-272 ; Drug: Paclitaxel; Administered IV, on days 1, 8, 15 of 28 day cycle.
Experimental: Nera 240 + Pac Neratinib 240 mg + Paclitaxel 80 mg/m^2	Drug: Neratinib; Administered orally, continuous, once daily.; Other Names: HKI-272 ; Drug: Paclitaxel; Administered IV, on days 1, 8, 15 of 28 day cycle.

Outcome Measures

Primary Outcome Measures

1. Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events [From first dose day through day 28.]

   The incidence of DLTs in subjects with advanced solid tumors, treated with neratinib in combination with paclitaxel 80 mg/m^2. DLT was defined as any neratinib plus paclitaxel related Grade 3 or 4 nonhematologic toxicity or Grade 4 hematologic toxicity with few exceptions.

2. Maximum Tolerated Dose [From first dose day through day 28.]

   The maximum tolerated dose of neratinib, as determined by the incidence of DLTs, in combination with paclitaxel 80 mg/m^2, in subjects with advanced solid tumors.

Secondary Outcome Measures

1. Objective Response Rate [From first dose date to progression/death or last tumor assessment, up to 78 weeks.]

   Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.

2. Progression Free Survival [From first dose date to progression/death, up to 78 weeks.]

   Number of weeks between the date of the first dose of test article and the first date of disease recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), as at least a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as reference the nadir LD, meaning the smallest sum of the LDs recorded since the treatment started; or unequivocal progression of existing nontarget lesions; or the appearance of any new lesions.

3. Duration of Response [From start date of response to first disease progression, up to 71 weeks.]

   Number of weeks from the time at which measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever status is recorded first) until the first date on which recurrence or progressive disease (PD) is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started, for responders only, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must have confirmed pathologic diagnosis of a solid tumor that is not curable with available therapy for which HKI-272 plus paclitaxel is a reasonable treatment option.

• At least 1 measurable lesion as defined by RECIST criteria.

• Eastern Cooperative Oncology Group (ECOG) 0 to 1

• LVEF within institutional limits of normal (by MUGA or ECHO).

• Screening laboratory values within the following parameters:

• ANC: greater than or equal to 1.5 x 10E9 /L (1,500 /mm3)

• Platelet count: 10 x 10E10 /L (100,000 /mm3)

• Hemoglobin: greater than or equal to 9.0 g/dL

• Serum creatinine: less than or equal to 1.5 x upper limit of normal (ULN)

• Total bilirubin: less than or equal to 1.5 xULN · AST and ALT: less than or equal to 2.5 xULN (less than or equal to 5 x ULN if liver metastases are present)

• For women of child bearing potential, a negative urine or serum pregnancy test result before study entry. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or other means of birth control or whose sexual partners are either sterile or using contraceptives.

• All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control for the duration of the study and for 28 days after the last dose of test article.

Exclusion Criteria:

• Prior treatment with anthracyclines with a cumulative dose of doxorubicin of greater than 400 mg/m^{2, epirubicin dose of greater than 800 mg/m}2, or the equivalent dose for other anthracyclines or derivatives.

• Major surgery, chemotherapy, radical (curative intent) radiotherapy, investigational agents, or other cancer therapy within 2 weeks of treatment day 1 or non-recovery from all clinically significant acute adverse effects of prior therapies (excluding alopecia).

• Subjects with bone or skin as the only site of disease.

• Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (subjects with a history of CNS metastases or cord compression are allowable if they have been definitively treated and have been clinically stable for at least three months, and off steroids or anticonvulsants, before first dose of test article).

• QTc interval greater than 0.47 second or known history of QTc prolongation or Torsade de Pointes (TdP).

• Known hypersensitivity to paclitaxel or Cremophor EL (polyoxyethylated castor oil).

• Pregnant or breast feeding women.

• Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade greater than or equal to 2 diarrhea of any etiology at baseline).

• Inability or unwillingness to swallow the HKI-272.

• Treatment with a taxane within 3 months of treatment day 1.

• Pre-existing grade 2 or greater motor or sensory neuropathy.

• Any other cancer within 5 years prior to screening with the exception of contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin.

• Presence of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association [NYHA] functional classification of greater than or equal to 2), angina requiring treatment, myocardial infarction within the past 12 months, or any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention.

• Evidence of significant medical illness or abnormal laboratory finding that would, in the investigator's judgment, make the subject inappropriate for this study. Examples include, but are not limited to, serious active infection (ie, requiring intravenous antibiotic or antiviral agent), uncontrolled major seizure disorder, or significant pulmonary disorder (e.g. interstitial pneumonitis, pulmonary hypertension).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site	Shizuoka		Japan
2	Investigational Site	Tokyo		Japan

Sponsors and Collaborators

• Puma Biotechnology, Inc.

Investigators

• Study Director: Puma, Biotechnology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT00768469
• Other Study ID Numbers: 3144A2-1115 / B1891001
• First Posted: Oct 8, 2008
• Last Update Posted: Nov 19, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by Puma Biotechnology, Inc.: HKI-272; Paclitaxel; Combination; Solid Tumor
• Additional relevant MeSH terms: Neoplasms; Paclitaxel

Study Results

Participant Flow

Arm/Group Title	Nera 160 + Pac	Nera 240 + Pac
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2	Neratinib 240 mg + Paclitaxel 80 mg/m^2
Period Title: Overall Study
STARTED	3	7
COMPLETED	0	0
NOT COMPLETED	3	7

Baseline Characteristics

Arm/Group Title	Nera 160 + Pac	Nera 240 + Pac	Total
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2	Neratinib 240 mg + Paclitaxel 80 mg/m^2	Total of all reporting groups
Overall Participants	3	7	10
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	6 85.7%	9 90%
>=65 years	0 0%	1 14.3%	1 10%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.67 (10.12)	53.14 (8.07)	52.10 (8.31)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	7 100%	9 90%
Male	1 33.3%	0 0%	1 10%
Race/Ethnicity, Customized (Count of Participants)
Japanese	3 100%	7 100%	10 100%

Outcome Measures

1. Primary Outcome

Title	Dose Limiting Toxicity (DLT) - Percentage of Participants With DLT Events
Description	The incidence of DLTs in subjects with advanced solid tumors, treated with neratinib in combination with paclitaxel 80 mg/m^2. DLT was defined as any neratinib plus paclitaxel related Grade 3 or 4 nonhematologic toxicity or Grade 4 hematologic toxicity with few exceptions.
Time Frame	From first dose day through day 28.

Outcome Measure Data

Analysis Population Description

Patients with at least one dose of neratinib.

Arm/Group Title	Nera 160 + Pac	Nera 240 + Pac
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2	Neratinib 240 mg + Paclitaxel 80 mg/m^2
Measure Participants	3	7
Number [percentage of participants.]	0 0%	0 0%

2. Secondary Outcome

Title	Objective Response Rate
Description	Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.
Time Frame	From first dose date to progression/death or last tumor assessment, up to 78 weeks.

Outcome Measure Data

Analysis Population Description

Subjects who met the eligibility criteria, received at least 2 weeks of neratinib and at least 2 doses of paclitaxel, and underwent at least 1 follow-up tumor assessment at approximately cycle 2 (week 8). In the case of disease progression prior to week 8, a clinical assessment of progressive disease (PD) was adequate.

Arm/Group Title	Nera 160 + Pac	Nera 240 + Pac
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2	Neratinib 240 mg + Paclitaxel 80 mg/m^2
Measure Participants	3	6
Number (95% Confidence Interval) [percentage of participants]	33.3 1110%	50.0 714.3%

3. Secondary Outcome

Title	Progression Free Survival
Description	Number of weeks between the date of the first dose of test article and the first date of disease recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (v1.0), as at least a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as reference the nadir LD, meaning the smallest sum of the LDs recorded since the treatment started; or unequivocal progression of existing nontarget lesions; or the appearance of any new lesions.
Time Frame	From first dose date to progression/death, up to 78 weeks.

Outcome Measure Data

Analysis Population Description

Subjects who met the eligibility criteria, received at least 2 weeks of neratinib and at least 2 doses of paclitaxel, and underwent at least 1 follow-up tumor assessment at approximately cycle 2 (week 8). In the case of disease progression prior to week 8, a clinical assessment of progressive disease was adequate.

Arm/Group Title	Nera 160 + Pac	Nera 240 + Pac
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2	Neratinib 240 mg + Paclitaxel 80 mg/m^2
Measure Participants	3	6
Median (95% Confidence Interval) [weeks]	15.9	37.1

4. Secondary Outcome

Title	Duration of Response
Description	Number of weeks from the time at which measurement criteria are met for Complete Response (CR) or Partial Response (PR) (whichever status is recorded first) until the first date on which recurrence or progressive disease (PD) is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started, for responders only, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: CR, disappearance of all target lesions; PR, >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.
Time Frame	From start date of response to first disease progression, up to 71 weeks.

Outcome Measure Data

Analysis Population Description

Patients with Partial Response (PR) or Complete Response (CR) in the evaluable population.

Arm/Group Title	Nera 160 + Pac	Nera 240 + Pac
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2	Neratinib 240 mg + Paclitaxel 80 mg/m^2
Measure Participants	1	3
Median (95% Confidence Interval) [weeks]	70.1	33.1

5. Primary Outcome

Title	Maximum Tolerated Dose
Description	The maximum tolerated dose of neratinib, as determined by the incidence of DLTs, in combination with paclitaxel 80 mg/m^2, in subjects with advanced solid tumors.
Time Frame	From first dose day through day 28.

Outcome Measure Data

Analysis Population Description

Patients with at least one dose of neratinib.

Arm/Group Title	Nera + Pac
Arm/Group Description	Neratinib + Paclitaxel 80 mg/m^2
Measure Participants	10
Number [mg]	240

Adverse Events

Time Frame	From first dose to last dose plus 28 days, up to 78 weeks.
Adverse Event Reporting Description	Safety Population
Arm/Group Title	Nera 160 + Pac		Nera 240 + Pac
Arm/Group Description	Neratinib 160 mg + Paclitaxel 80 mg/m^2		Neratinib 240 mg + Paclitaxel 80 mg/m^2
All Cause Mortality
	Nera 160 + Pac		Nera 240 + Pac
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Nera 160 + Pac		Nera 240 + Pac
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		1/7 (14.3%)
Infections and infestations
Pneumonia	0/3 (0%)		1/7 (14.3%)
Other (Not Including Serious) Adverse Events
	Nera 160 + Pac		Nera 240 + Pac
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		7/7 (100%)
Blood and lymphatic system disorders
Anaemia	3/3 (100%)		5/7 (71.4%)
Leukopenia	3/3 (100%)		7/7 (100%)
Lymphopenia	1/3 (33.3%)		1/7 (14.3%)
Neutropenia	2/3 (66.7%)		6/7 (85.7%)
Thrombocytopenia	0/3 (0%)		1/7 (14.3%)
Cardiac disorders
Left ventricular dysfunction	0/3 (0%)		1/7 (14.3%)
Palpitations	0/3 (0%)		1/7 (14.3%)
Eye disorders
Dacryostenosis acquired	0/3 (0%)		1/7 (14.3%)
Diplopia	0/3 (0%)		1/7 (14.3%)
Dry eye	0/3 (0%)		1/7 (14.3%)
Eye discharge	0/3 (0%)		1/7 (14.3%)
Eyelid ptosis	0/3 (0%)		1/7 (14.3%)
Lacrimation increased	1/3 (33.3%)		0/7 (0%)
Vision blurred	0/3 (0%)		1/7 (14.3%)
Gastrointestinal disorders
Abdominal discomfort	0/3 (0%)		1/7 (14.3%)
Abdominal pain	0/3 (0%)		1/7 (14.3%)
Abdominal pain upper	1/3 (33.3%)		1/7 (14.3%)
Ascites	1/3 (33.3%)		0/7 (0%)
Colitis	0/3 (0%)		1/7 (14.3%)
Constipation	1/3 (33.3%)		1/7 (14.3%)
Diarrhoea	3/3 (100%)		7/7 (100%)
Dyspepsia	2/3 (66.7%)		0/7 (0%)
Ileus	0/3 (0%)		1/7 (14.3%)
Nausea	1/3 (33.3%)		5/7 (71.4%)
Stomatitis	1/3 (33.3%)		5/7 (71.4%)
Vomiting	1/3 (33.3%)		3/7 (42.9%)
General disorders
Catheter site pain	1/3 (33.3%)		0/7 (0%)
Chest pain	0/3 (0%)		1/7 (14.3%)
Fatigue	2/3 (66.7%)		7/7 (100%)
Influenza like illness	2/3 (66.7%)		2/7 (28.6%)
Injection site reaction	1/3 (33.3%)		0/7 (0%)
Oedema peripheral	0/3 (0%)		1/7 (14.3%)
Pain	1/3 (33.3%)		1/7 (14.3%)
Pyrexia	0/3 (0%)		1/7 (14.3%)
Immune system disorders
Contrast media allergy	0/3 (0%)		1/7 (14.3%)
Infections and infestations
Adenoiditis	0/3 (0%)		1/7 (14.3%)
Cellulitis	0/3 (0%)		1/7 (14.3%)
Cystitis	2/3 (66.7%)		2/7 (28.6%)
Fungal skin infection	0/3 (0%)		1/7 (14.3%)
Herpes virus infection	0/3 (0%)		1/7 (14.3%)
Nasopharyngitis	1/3 (33.3%)		0/7 (0%)
Paronychia	1/3 (33.3%)		3/7 (42.9%)
Pharyngitis	0/3 (0%)		1/7 (14.3%)
Pneumonia	0/3 (0%)		1/7 (14.3%)
Pneumonia bacterial	0/3 (0%)		1/7 (14.3%)
Sinusitis	1/3 (33.3%)		0/7 (0%)
Upper respiratory tract infection	0/3 (0%)		1/7 (14.3%)
Urinary tract infection	1/3 (33.3%)		0/7 (0%)
Investigations
Alanine aminotransferase increased	1/3 (33.3%)		0/7 (0%)
Aspartate aminotransferase increased	1/3 (33.3%)		1/7 (14.3%)
Blood alkaline phosphatase increased	1/3 (33.3%)		1/7 (14.3%)
Blood creatinine increased	1/3 (33.3%)		1/7 (14.3%)
Blood lactate dehydrogenase increased	1/3 (33.3%)		1/7 (14.3%)
Blood potassium increased	1/3 (33.3%)		0/7 (0%)
Brain natriuretic peptide increased	1/3 (33.3%)		0/7 (0%)
C-reactive protein increased	0/3 (0%)		2/7 (28.6%)
Electrocardiogram abnormal	1/3 (33.3%)		1/7 (14.3%)
Weight decreased	0/3 (0%)		3/7 (42.9%)
Metabolism and nutrition disorders
Decreased appetite	1/3 (33.3%)		5/7 (71.4%)
Dehydration	0/3 (0%)		1/7 (14.3%)
Hyponatraemia	0/3 (0%)		1/7 (14.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)		1/7 (14.3%)
Arthritis	0/3 (0%)		1/7 (14.3%)
Back pain	1/3 (33.3%)		0/7 (0%)
Musculoskeletal stiffness	0/3 (0%)		1/7 (14.3%)
Myalgia	0/3 (0%)		2/7 (28.6%)
Pain in extremity	0/3 (0%)		1/7 (14.3%)
Nervous system disorders
Dizziness	0/3 (0%)		1/7 (14.3%)
Dysgeusia	2/3 (66.7%)		3/7 (42.9%)
Headache	1/3 (33.3%)		2/7 (28.6%)
Peripheral sensory neuropathy	2/3 (66.7%)		6/7 (85.7%)
Somnolence	0/3 (0%)		1/7 (14.3%)
Psychiatric disorders
Insomnia	0/3 (0%)		1/7 (14.3%)
Mood altered	0/3 (0%)		1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
Cough	1/3 (33.3%)		0/7 (0%)
Dyspnoea	0/3 (0%)		2/7 (28.6%)
Epistaxis	0/3 (0%)		2/7 (28.6%)
Pharyngeal erythema	1/3 (33.3%)		0/7 (0%)
Upper respiratory tract inflammation	0/3 (0%)		1/7 (14.3%)
Skin and subcutaneous tissue disorders
Alopecia	3/3 (100%)		5/7 (71.4%)
Dermatitis acneiform	1/3 (33.3%)		0/7 (0%)
Dry skin	0/3 (0%)		3/7 (42.9%)
Eczema	1/3 (33.3%)		0/7 (0%)
Nail disorder	1/3 (33.3%)		3/7 (42.9%)
Prurigo	1/3 (33.3%)		3/7 (42.9%)
Pruritus	1/3 (33.3%)		1/7 (14.3%)
Rash	1/3 (33.3%)		3/7 (42.9%)
Skin fissures	1/3 (33.3%)		1/7 (14.3%)
Urticaria	1/3 (33.3%)		0/7 (0%)
Vascular disorders
Flushing	1/3 (33.3%)		1/7 (14.3%)
Thrombophlebitis	1/3 (33.3%)		0/7 (0%)

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.