HKI-272

Progression Free Survival (PFS), Measured in Months, for Randomized Subjects of the Central Assessment. The time interval from the date of randomization until the first date on which recurrence, progression (per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) v1.1), or death due to any cause, is documented. For subjects without recurrence, progression or death, it is censored at the last valid tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 24 months.

Overall survival (OS) is defined as the time from randomization to death due to any cause, censored at the last date known alive on or prior to the data cutoff employed for the analysis, whichever was earlier. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 48 months.

Invasive disease-free survival time is defined as the time from date of randomization until the first disease recurrence of the following events: invasive ipsilateral breast tumor recurrence, invasive contralateral breast cancer, local/regional invasive recurrence, distant recurrence and death from any cause.

Defined as the percentage of patients achieving a complete response (CR) or partial response (PR) of Central Nervous System (CNS) lesions based on composite criteria, reported separately in Cohorts 1, 3A, 3B. For the volumetric criteria, an objective CR will be defined as the following: Disappearance of all CNS target and non-target lesions sustained for at least 4 weeks; no new lesions; stable or decreasing steroid dose; stable or improved neurological symptoms. An objective PR by volumetric criteria will be defined as the following: At least a 50% decrease in the sum volume of CNS target lesions, taking as reference the baseline sum volume sustained for at least 4 weeks; no new lesions; stable or decreasing steroid dose; stable or improved neurological symptoms.

Defined as the percentage of patients achieving a complete response (CR) or partial response (PR) of Central Nervous System (CNS) lesions based on RANO-BM criteria, reported separately in Cohorts 4A, 4B, and 4C. For the RANO-BM criteria, an objective CR will be defined as the following: Disappearance of all CNS target and non-target lesions sustained for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. An objective PR by RANO-BM criteria will be defined as the following: At least a 30% decrease in the sum LD of CNS target lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically.

Percentage of participants with clinically assessed grade 3 or greater diarrhea reported within the first 2 cycles (each cycle is 21 days) of neratinib while using anti-diarrheal strategies. Reports of diarrhea will be graded according to NCI CTCAE version 4.0.

Percentage of participants who did not require loperamide during cancer treatment for at least 5 cycles will be reported.

The percentage of participants who discontinued all anti-diarrheal medications during cancer treatment for at least 5 cycles will be reported.

Percentage of participants with reported serious adverse events and adverse events of interest of any grade that have been determined to be related to the anti-diarrhea treatment will be reported by worst grade and associated toxicity.

The number of participants who experienced a dose hold of neratinib during the course of study therapy will be reported

The number of participants who discontinued neratinib earlier than expected during the course of study therapy will be reported

The number of participants whose dose was reduced at any time during the course of therapy will be reported

* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

* Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter. * Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. * Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. * Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.

The proportion of patients who discontinue the treatment with neratinib due to diarrhoea within this time period.

pCR is defined as the lack of all signs of invasive cancer in the breast removed during surgery

The primary endpoint is to describe the changes in colon pathology between the baseline colonoscopy and the second colonoscopy.

The primary objective of this study is to characterize the percentage of patients with Grade 3 or higher diarrhea in patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with intensive loperamide prophylaxis, after prior treatment with trastuzumab. Grade 3: Increase of \>=7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self care ADL. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death.

ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.

Defined as the interval from the date of randomization until the first date on which recurrence or progression, or death due to any cause, is documented, censored at the last assessable evaluation or at the initiation of new anticancer therapy.

Progression Free Survival, Measured in Months, for Subjects Randomized. Investigator assessment. The time interval from the date of randomization until the earliest date of progression per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) or death due to any cause. For subjects without death or progression, censorship was at the last valid tumor assessment.

16 week progression-free survival (PFS) rate of neratinib in women with human epidermal growth factor receptor 2 (HER2) positive breast cancer, either with prior trastuzumab or no prior trastuzumab therapy, evaluated by independent assessment of tumor scans collected at baseline and then every 8 weeks.

Objective response rate as reported by Independent Assessment (radiographic review by independent radiologists) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: 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.

The RP2D will be identified during the phase 1 dose escalation portion of the study using a modified 3+3 design and evaluated in a phase 1b dose expansion cohort of up to 12 patients with platinum-resistant ovarian cancer.

Phase 1b: To evaluate clinical benefit (≥4-month progression-free survival \[PFS\]) of niraparib and neratinib given at the RP2D to in patients with platinum-resistant ovarian cancer. To evaluate the clinical benefit, (defined as ≥4-month progression free survival (PFS), using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria in patients with platinum-resistant ovarian cancer.

RP2D for the combination of neratinib and sodium valproate that is less than or the same as the maximum tolerated dose (MTD).

ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.

DLT was defined as 1. Grade 3 or 4 non-hematologic toxicity (exceptions listed below as a.-c.), a. Grade 3 asthenia was NOT considered to be a DLT UNLESS it lasted \>3 days. b. Grade 3 nausea or vomiting was NOT considered to be a DLT UNLESS the subject was already receiving optimal medical therapy. c. Grade 3 or 4 infection was NOT considered to be a DLT UNLESS it is associated with grade 3 or 4 neutropenia. 2. Grade 3 diarrhea that lasted \>2 days while the subject was on optimal medical therapy or that was associated with fever (greater than or equal 38.0 ºC) or grade 3 dehydration. 3. Grade 4 neutropenia lasting ≥3 days or grade 4 febrile neutropenia. 4. Grade 4 thrombocytopenia lasting ≥3 days or complicated with bleeding or requiring platelet transfusion. 5. Delayed recovery (to National Cancer Institute \[NCI\] grade 1 or less, or baseline) from any of the toxicities listed above (items 1-4), that was related to study drug, and that delayed the next dose by more than 3 weeks.

Six subjects will be initially enrolled (neratinib 240 mg/day; capecitabine 1500 mg/m²/day on days 1 through 14). AEs and DLTs will be assessed from the first dose of investigational product through day 21. Based on the DLT rate in these first 6 subjects, dose tolerability will be confirmed as follows: If ≤1 of the first 6 evaluable subjects experience a DLT by day 21, then this dose is considered tolerable, and enrollment will stop. If ≥3 of the first 6 evaluable subjects experience a DLT by day 21, this dose is considered intolerable. If 2 of the first 6 evaluable subjects experience a DLT by day 21, then an additional 4 subjects will be enrolled at the same dose level. If a total of 10 subjects are enrolled, then the tolerability will be confirmed as follows: If ≤3 of the total 10 subjects experience a DLT by day 21, then this dose will be considered tolerable. If ≥4 of the total 10 subjects experience a DLT by day 21, then the dose will be considered intolerable.

Number of participants experiencing DLT of neratinib in combination with vinorelbine in Japanese patients.

A DLT was defined as any dose-limiting Adverse Event related to neratinib + Temsirolimus as Grade 3 or higher nonhematologic toxicity (except neutropenia) or Grade 3 or higher diarrhea lasting \>2 days with optimal antidiarrheal therapy etc.

Identification of the daily neratinib high-dose MTD in combination with weekly temsirolimus.

Identification of the weekly temsirolimus high-dose MTD in combination with daily neratinib

A DLT was defined as any dose-limiting adverse event (AE) related to neratinib + TEMSR as follows: \[1\] Grade 3 or 4 nonhematologic toxicity (Grade 3 or 4 nausea, vomiting, hyperglycemia, hypophosphatemia, hypertriglyceridemia, or hypercholesterolemia was not considered a DLT unless the subject was already receiving optimal medical therapy). \[2\] Grade 3 or 4 diarrhea lasting \>2 days while subject was on optimal vigorous antidiarrheal therapy. \[3\] Grade 4 neutropenia lasting \>3 days or Grade 3 or 4 neutropenia of any duration with sepsis or a fever \>38.5C. \[4\] Platelet value less than or equal to 25,000/mm3 or bleeding requiring a platelet transfusion. \[5\] Delayed recovery from toxicity, which delayed rescheduled re-treatment for \>3 weeks. \[6\] Inability to maintain the original dose during the first 28 days of treatment (at least 21 doses of neratinib and 2 doses of TEMSR at the original specified dose) due to treatment-related toxicity.

Number of participants reporting Adverse Events Causing Dose Limiting Toxicities (DLT).

MTD reflects the highest dose of neratinib plus capeciteabine that did not cause a selected Grade 3 toxicity in \>= 2 participants, which is any of 1) Grade 3 or 4 non-hematologic toxicity (Grade 3 asthenia was not considered a DLT unless lasting \>3 days, 2) Grade 3 diarrhea lasting \>2 days on optimal medical therapy or associated with fever or dehydration. 3) Grade 4 neutropenia lasting ≥ 3 days or Grade 4 febrile neutropenia, 4) Grade 4 thrombocytopenia lasting ≥3 days or associated with bleeding or requiring platelet transfusion, 5) Delayed recovery \[to ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline\] from one of the above listed toxicities that were related to neratinib and/or capecitabine that delayed the initiation of the next dose by more than 3 weeks.

MTD reflects the highest dose of capecitabine in combination with neratinib that did not cause a selected Grade 3 toxicity in \>= 2 participants, which is any of 1) Grade 3 or 4 non-hematologic toxicity (Grade 3 asthenia was not considered a DLT unless lasting \>3 days, 2) Grade 3 diarrhea lasting \>2 days on optimal medical therapy or associated with fever or dehydration. 3) Grade 4 neutropenia lasting ≥ 3 days or Grade 4 febrile neutropenia, 4) Grade 4 thrombocytopenia lasting ≥3 days or associated with bleeding or requiring platelet transfusion, 5) Delayed recovery \[to ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline\] from one of the above listed toxicities that were related to neratinib and/or capecitabine that delayed the initiation of the next dose by more than 3 weeks.

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.

Overall Response Rate (ORR), subjects with CR or PR by independent review in subjects with ErbB-2-positive breast cancer treated at the MTD of neratinib in combination with vinorelbine per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.0: 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.

Dose Limiting Toxicity in subjects with solid tumors treated with neratinib, administered daily, in combination with paclitaxel 80 mg/m² IV on days 1, 8, and 15 of a 28 day cycle.

Subjects with partial response (PR) or complete response (CR) with ERBB2 positive breast cancer treated at the maximum tolerated dose (MTD) of neratinib in combination with paclitaxel, 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 no progressive disease (PD) for non-target lesions, and no new lesions.

16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.

MTD is defined as the prior dose level of the dose level which has \>=2 of 3 to 6 subjects that experience a neratinib-related DLT during 21 days from first dose date. A DLT is defined as any HKI-272-related nonhematologic grade 3 or any grade 4 AE according to the Common Terminology Criteria for Adverse Events version 3.0 except: Grade 3 nausea, vomiting, diarrhea, or rash unless subject was receiving appropriate medical therapy.