Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

All Drugs and Chemicals

Osimertinib

* Cohort 1: Previously treated participants with EGFR exon 20 insertion mutant positive NSCLC (closed to enrollment)
* Cohort 2: Previously treated participants with HER2 exon 20 insertion mutant positive NSCLC (closed to enrollment)
* Cohort 3: Treatment naïve participants with EGFR exon 20 insertion-mutant positive NSCLC (fully enrolled)
* Cohort 4: Treatment naïve participants with HER2 exon 20 insertion mutant positive NSCLC
* Cohort 5: Participants who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed
* Cohort 6: Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib
* Cohort 7: Participants with EGFR or HER2 activating mutations

The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.

* Cohorts 1-3: 16 mg QD
* Cohort 4: 8 mg BID
* Cohort 5: randomized to 8 mg BID or 6 mg BID or 10 mg QD
* Cohorts 6 and 7: 8 mg BID

Poziotinib

This is a Phase 2, open-label, multi-center study to evaluate the efficacy and the safety/tolerability of poziotinib in seven participant cohorts for up to 603 previously treated and treatment-naïve NSCLC participant. Cohorts 3 and 4 were added with Amendment 1 and three additional cohorts were added with Amendment 2 (Cohorts 5, 6 and 7).

The Screening period (Day -30 to Day -1) lasts up to approximately 30 days prior to Cycle 1, Day 1. Participant must meet all Inclusion/Exclusion Criteria to participate in the study. Eligible participants will provide written Informed Consent prior to undergoing any study procedures.

Each treatment cycle is 28 calendar days in duration. There will be seven participant cohorts and eligible participants will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status:

* Cohort 1: Previously treated participant with EGFR exon 20 insertion mutation positive NSCLC (complete)
* Cohort 2: Previously treated participant with HER2 exon 20 insertion mutation positive NSCLC (complete)
* Cohort 3: Treatment naïve participant with EGFR exon 20 insertion mutation positive NSCLC (complete)
* Cohort 4: Treatment naïve participant with HER2 exon 20 insertion mutation positive NSCLC (fully enrolled)
* Cohort 5: Participants who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed (closed to enrollment)
* Cohort 6: Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib (closed to enrollment)
* Cohort 7: Participants with EGFR or HER2 activating mutations (closed to enrollment)

Toxicity will be assessed based on the grade of the adverse events using CTCAE version 4.03.

On Day 1 of each 28-day cycle, the participant's absolute neutrophil count (ANC) must be ≥1.5×10\^9/L and platelet count must be ≥100×10\^9/L before administering poziotinib. All participants will be treated until disease progression (except for first progression in Cohort 5), death, intolerable adverse events (AEs), or other protocol-specified reasons for participant withdrawal.

Each treatment cycle is 28 calendar days in duration. There will be seven participant cohorts and eligible participants will be enrolled into each cohort in parallel based on EGFR or HER2 exon 20 mutation status and prior treatment status:

* Cohort 1: Previously treated participants with EGFR exon 20 insertion mutant positive NSCLC (closed to enrollment)
* Cohort 2: Previously treated participants with HER2 exon 20 insertion mutant positive NSCLC (closed to enrollment)
* Cohort 3: Treatment naïve participants with EGFR exon 20 insertion mutant positive NSCLC (fully enrolled)
* Cohort 4: Treatment naïve participants with HER2 exon 20 insertion mutant positive NSCLC
* Cohort 5: Participants who meet the criteria for enrollment in Cohort 1 to 4, but the enrollment in the respective cohort has been closed
* Cohort 6: Participants with acquired EGFR mutation who progressed while on treatment with first-line osimertinib
* Cohort 7: Participants with EGFR or HER2 activating mutations

Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation

A Phase 2 Study of Poziotinib in Patients With Non-Small Cell Lung Cancer (NSCLC), Locally Advanced or Metastatic, With EGFR or HER2 Exon 20 Insertion Mutation (ZENITH20)

Number of days from the treatment start date to the date of documented disease progression or death due to any cause.

The proportion of subjects who achieve Complete Response (CR) and Partial Response (PR) by the best response from the first dose of poziotinib to the end of study.

The proportion of subjects who achieve CR, PR, and Stable Disease (SD) by the best response from the first dose of poziotinib to the end of study.

Number of days from the date that measurement criteria are first met for CR or PR (whichever status is recorded first) until the first subsequent date that progressive disease or death is documented.

Spectrum Pharmaceuticals, Inc

Carboplatin

Pemetrexed

Cisplatin

Mitogens

Part A: Safety Lead-In Approximately 6-12 patients will receive zipalertinib administered at an initial dose of zipalertinib PO BID (Dose Level 1) in combination with pemetrexed and carboplatin or cisplatin on a 21-day cycle. Patients may continue to receive study treatment until documentation of progressive disease (PD) or until other withdrawal criteria are met, whichever comes first.

Enrollment into the Phase 3 portion of the study will begin following completion of Part A.

Approximately 260 patients will be randomized on a 1:1 basis to receive pemetrexed and a platinum agent (either carboplatin or cisplatin) with or without zipalertinib on a 21-day cycle.

Carboplatin or cisplatin will be administered for 4 cycles. Patients may continue to receive zipalertinib (experimental study arm) and pemetrexed (both study arms) until documentation of PD or until other withdrawal criteria are met, whichever comes first.

TAS6417

Taiho Oncology, INC

Ramalingam Ratnasabapathy

Nashat Gabrail

Yutaka Fujiwara

Hisashi Tanaka

Masafumi Yamaguchi

Katsuhiko Naoki

Satoshi Ikeda

Yoshihiko Sakata

Shunichi Sugawara

Kadoaki Ohashi

Takayasu Kurata

Akihiro Tamiya

Ryo Ariyasu

Haruko Daga

Takako Inoue

Sayed Hashemi

Santiago Viteri Ramírez

Florencia Garcia Casabal

Ana Laura Ortega-Granados

Francisco Javier de Castro Carpeno

The purpose of this study is to evaluate the safety and efficacy of zipalertinib in combination with standard first-line platinum-based chemotherapy compared to chemotherapy alone, in patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations.

This study will evaluate the efficacy and safety of zipalertinib in combination with standard chemotherapy with pemetrexed and a platinum agent (either carboplatin or cisplatin) in patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations.

The study will be conducted in two parts:

* Part A: Safety lead-in to determine the recommended dose of zipalertinib in combination with standard chemotherapy pemetrexed and a platinum agent (either carboplatin or cisplatin) to be studied in Part B of the study.
* Part B: Randomized, controlled, open-label, multinational Phase 3 study to assess the efficacy and safety of zipalertinib in combination with standard chemotherapy with pemetrexed and a platinum agent (either carboplatin or cisplatin) compared to standard chemotherapy alone. Patients randomized to the chemotherapy-only treatment arm in Part B may receive treatment with zipalertinib as monotherapy after BICR-assessed progressive disease (PD) is documented (optional "crossover arm").

An independent data monitoring committee (IDMC) will be established to monitor interim safety Data.

A treatment cycle is defined as 21 days for both parts of the study.

Part A: Safety Lead-In The primary objective of Part A is to determine the recommended dose of zipalertinib administered in combination with pemetrexed and a platinum agent (either carboplatin or cisplatin) to be studied in the Phase 3 portion of this study.

Approximately 6-12 patients will receive zipalertinib administered at an initial dose of zipalertinib PO BID (Dose Level 1) in combination with pemetrexed and carboplatin or cisplatin on a 21-day cycle. Patients may continue to receive study treatment until documentation of progressive disease (PD) or until other withdrawal criteria are met, whichever comes first. Patients will be enrolled using a rolling-6 design,35 and the determination of the dose of zipalertinib to be used in Part B of the study will be informed by the incidence of dose-limiting toxicities (DLTs) observed during Cycle 1.

Part B: Phase 3 Enrollment into the Phase 3 portion of the study will begin following completion of Part A.

Approximately 260 patients will be randomized on a 1:1 basis to receive pemetrexed and a platinum agent (either carboplatin or cisplatin) with or without zipalertinib on a 21-day cycle.

Carboplatin or cisplatin will be administered for 4 cycles. Patients may continue to receive zipalertinib (experimental study arm) and pemetrexed (both study arms) until documentation of PD or until other withdrawal criteria are met, whichever comes first.

REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors)

Randomized, Controlled, Open-label, Phase 3, Global Multi - Center Trial to Assess the Efficacy and Safety of Zipalertinib Plus Chemotherapy Versus Chemotherapy Alone, in Patients With Previously Untreated, Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion (ex20ins) Mutations

The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results into a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state. This scale is numbered from 0 to 100. The higher the score the better the outcome

The EORTC QLQ-C30 is a "core questionnaire" which incorporates a range of physical, emotional and social health developed to assess the quality of life of cancer patients. This scale is numbered from 30 to 130. The higher the score equates to better functioning.

The NSCLC- SAQ was developed to incorporate the patient's perspective into evaluation of clinical benefit in advanced non-small cell lung cancer trials.. Qualitative evidence supports 7 items covering 5 symptom concepts with the total score measuring overall severity of the following NSCLC symptoms: cough, pain, dyspnea, fatigue, and appetite. Lower scores indicate lower symptom severity.

Taiho Oncology, Inc.

Digestive System Diseases

Skin and Connective Tissue Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Rare Diseases

Stomach Neoplasms

Breast Neoplasms

Urinary Bladder Neoplasms

Stomach Cancer

Biliary Tract Cancer

Herbal and Botanical

Cola

In Part A, cohorts of patients with select HER2, HER3, or EGFR alterations will receive increasing doses of BDTX-189. It is expected that up to approximately 70 patients will be enrolled in this dose escalation arm. If an alternative schedule is explored, up to 24 additional patients may be enrolled.

In Part B, patients with a solid tumor harboring specific allosteric HER2 mutations or an HER2 or EGFR exon 20 insertion mutation will receive the recommended Phase 2 dose of BDTX-189. It is expected that approximately 100 participants will be enrolled in this phase 2 portion.

Participants will receive a daily, oral dose of BDTX-189 as part of a 3 week cycle.

BDTX-189

This is a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that have select mutations or alterations in human epidermal growth factor receptor 2 (HER2/ErbB2) genes or epidermal growth factor receptor (EGFR/ErbB1). The main goals of this study are to:

* Find the recommended dose of BDTX-189 that can be given safely to participants
* Learn more about the side effects of BDTX-189
* Learn what the body does to BDTX-189 after it has been taken (pharmacokinetics or PK)
* Determine the antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

BDTX-189 is an irreversible, small molecular inhibitor that is highly selective versus wild-type EGFR and potent for cancer driver mutations of the ErbB family, including extracellular, transmembrane, and kinase domain allosteric mutations of HER2, as well as EGFR and HER2 exon 20 insertion mutations. These allosteric ErbB mutations are found in 1 - 2 % of most solid tumors and enriched in some cancers with a prevalence of about 2 - 7% such as in non-small cell lung cancer, breast cancer, colorectal cancer, bladder cancer, and endometrial cancer. Currently approved HER2 and EGFR directed therapies are not active against the spectrum of allosteric mutations at relevant and tolerated exposure levels.

This Phase 1/2 multi-center, open-label trial is a first-in-human study that will evaluate BDTX-189 orally administered daily as a single agent in patients with solid tumors harboring select mutations or alterations. The Phase 1 portion is a dose escalation primarily designed to assess the safety and tolerability of BDTX-189 and to determine a recommended Phase 2 dose (RP2D). Phase 1 will focus on patients with a solid tumor with alterations such as:

* Allosteric HER2 or HER3 mutation(s)
* EGFR or HER2 exon 20 insertion mutation(s)
* HER2 amplified or overexpressing tumors
* EGFR exon 19 deletion or L858R mutation

Following selection of the RP2D, a Phase 2 portion will be initiated to further evaluate the clinical activity of BDTX-189. Phase 2 will focus on patients with a solid tumor harboring an:

* Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I)
* EGFR or HER2 exon 20 insertion mutation

Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory.

A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors.

MasterKey-01: A Phase 1/2, Open-label, Two-part, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics & Antitumor Activity of BDTX-189, an Inhibitor of Allosteric ErbB Mutations, in Patients w/ Advanced Solid Malignancies

Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

Objective response rate is defined as the proportion of participants who achieve a confirmed complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state.

Objective response is defined as the proportion of participants who achieved a complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Duration of response is the time from first documentation of a response to first evidence of progressive disease per RECIST version 1.1 or death. A response is defined as either a complete response (CR; disappearance of all target lesions and non-target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions). Progressive disease is defined by a target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions.

Disease control rate is defined as the proportion of participants achieving: a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; at least a 30% decrease in the sum of diameters of target lesions), or stable disease (SD; neither sufficient shrinkage to qualify for a PR nor sufficient increase in lesions) per RECIST version 1.1.

Progression-free survival is the time from first study dose until disease progression (PD; target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions) per RECIST v1.1.

Overall survival is the time from first study dose until death from any cause or study discontinuation.

Black Diamond Therapeutics, Inc.

Poziotinib will be taken by the patient orally, once daily with food and a glass of water at approximately the same time. The dose will be the last dose received or at the standard starting dose of 16 mg poziotinib. If a dose is missed, it may be taken any time during the day preferably with food, but at least 8 hours prior to the next scheduled dose.

This is an open-label extension study (Extension Study) designed to allow patients to continue to receive poziotinib treatment who have had previous exposure to poziotinib and/or are still receiving clinical benefit from treatment, as judged by the Investigator or treating physician. Patients must begin treatment in this study within 28 days after their last dose of poziotinib.

This extension protocol is intended to provide clinical benefit of poziotinib to patients who are responding to treatment. The additional treatment is optional and voluntary.

Patients who wish to participate in the extension study must provide written Informed Consent. Treatment will begin after completion of the End of Study (EOS) or End of Treatment (EOT) visit of the Original Study. The assessments obtained at the EOS or EOT visit will serve as Baseline data for the extension study.

Patients will continue to receive poziotinib treatment at the last dose received or at the standard starting dose of 16 milligrams (mg) poziotinib, once daily.

Patients may receive treatment as long as the patient is deriving clinical benefit, as judged by the investigator or treating physician (case-by-case decision with approval of Spectrum), death, withdrawal of consent, unacceptable toxicity, lost to follow-up, or poziotinib receives commercial approval in their country of residence or development is terminated by the Sponsor, whichever occurs first. There will be an EOS Visit 35 (±5) days after the last dose of poziotinib.

A Study to Allow Continued Dosing and/or Follow-up of Patients Who Have Had Previous Exposure to Poziotinib

An Open-Label Extension Study to Allow Continued Dosing and/or Follow-up of Patients Who Have Had Previous Exposure to Poziotinib

Number of patients with serious adverse events

Dose finding at 8 mg, 12 mg, or 16 mg of poziotinib once daily in 28-day treatment cycles.

Dose finding at 4 mg, 6 mg, or 8 mg of poziotinib twice daily in 28-day treatment cycles.

Once Daily or Twice Daily Dosing as determined in Phase 1 in 28-day treatment cycles.

Cohort 1: EGFR exon 20 insertion mutations

Cohort 2: HER2 exon 20 insertion mutations

The poziotinib drug substance is a hydrochloride salt of poziotinib and is formulated as a tablet for oral administration.

Poziotinib Once Daily Dosing

Poziotinib Twice Daily Dosing

Poziotinib Once Daily Dosing or Twice Daily Dosing as determined in Phase 1

A Phase 1/2, open-label, multicenter study to determine dose, tolerability, safety and efficacy of poziotinib in Japanese patients non-small cell lung cancer (NSCLC).

This is a Phase 1/2, open-label, multicenter study in Japanese patients with locally advanced or metastatic NSCLC. This study will be conducted in two parts. Phase 1 is designed to observe the maximum tolerated dose (MTD) or maximum administered dose (MAD) of poziotinib when administered once daily or twice daily. Phase 2 will evaluate the safety and efficacy of the dose determined in Phase 1. Study participation includes a 30 day screening period, up to 24 months of treatment, and long-term follow-up for a maximum of 24 months after discontinuation of study treatment.

Phase 1 will enroll up to 36 patients into a dose finding study with two parallel, randomized dose groups. Each group will undergo a dose-finding scheme using a 3+3 design with the assessment of dose-limiting toxicities (DLTs) at up to three dose levels. Patients will be randomized into once daily (QD) or twice daily (BID) dose groups. The DLT assessment will be conducted in the first cycle of treatment and therefore, poziotinib dose modifications are not permitted during this cycle. Patients will be hospitalized for the first 2 weeks.

Phase 2 will enroll 40 additional NSCLC patients with EGFR (20 patients) or HER2 (20 patients) exon 20 insertion mutations. Efficacy and safety of the dose and dosing regimen determined in Phase 1 will be evaluated. All patients will be treated in 28-day cycles for up to 24 months.

Phase 1 will have two randomized, parallel dose groups comparing daily dosing and twice daily dosing at 3 dose levels.

Phase 2 will be a single dose group evaluating the safety and efficacy of the dose determined in Phase 1 in 2 Cohorts. Cohort 1: EGFR exon 20 insertion mutations and Cohort 2: HER2 exon 20 insertion mutations.

Study of Poziotinib in Japanese Patients With NSCLC

A Phase 1/2 Dose Finding Study of Poziotinib in Japanese Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

The number of days from the treatment start date to the date of death due to any cause.

MTD/MAD will be assessed based on the occurrence of defined dose-limiting toxicities (DLT) and all available safety information during first cycle of treatment.

The proportion of patients who achieve Complete Response (CR) or Partial response (PR) by the best response from the first dose of poziotinib to the end of the study.

The proportion of patients who achieve CR, PR, and Stable Disease (SD) by the best response from the first dose of poziotinib to the end of the study.

The number of days from the date that measurement criteria are first met for CR or PR (whichever status is recorded first) until the first subsequent date that progressive disease or death is documented.

The number of days from the treatment start date to the date of documented disease progression or death.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation	NCT03318939	NSCLC	Poziotinib	18 Years -	Spectrum Pharmaceuticals, Inc
REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors)	NCT05973773	Advanced or Met...	TAS6417	18 Years -	Taiho Oncology, Inc.
A Study of BDTX-189, an Orally Available Allosteric ErbB Inhibitor, in Patients With Advanced Solid Tumors.	NCT04209465	Solid Tumor	BDTX-189	18 Years -	Black Diamond Therapeutics, Inc.
REZILIENT3 (REsearching ZIpaLertinib In Egfr Non-small Cell Lung Cancer Tumors)	NCT05973773	Advanced or Met...	TAS6417	18 Years -	Taiho Oncology, Inc.
A Study to Allow Continued Dosing and/or Follow-up of Patients Who Have Had Previous Exposure to Poziotinib	NCT03744715	NSCLC Breast Cancer	Poziotinib	18 Years -	Spectrum Pharmaceuticals, Inc
Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation	NCT03318939	NSCLC	Poziotinib	18 Years -	Spectrum Pharmaceuticals, Inc
Study of Poziotinib in Japanese Patients With NSCLC	NCT04402008	NSCLC	Poziotinib Once... Poziotinib Twic... Poziotinib Once...	20 Years -	Spectrum Pharmaceuticals, Inc

Spots Global Cancer Trial Database for exon 20 insertion mutation