Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Genomic Instability

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Myotonic Dystrophy Type 1

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Amino Acids

Trastuzumab

Paclitaxel

Carboplatin

Pemetrexed

Albumin-Bound Paclitaxel

Cisplatin

Immunomodulating Agents

Atezolizumab

Alectinib

Ado-Trastuzumab Emtansine

Vemurafenib

Adenosine

Maytansine

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tubulin Modulators

Antimitotic Agents

Immunotoxins

Immunoconjugates

Immunologic Factors

Tyrosine Kinase Inhibitors

Tyrosine

MPDL3280A 1200mg IV infusion - 3 weekly until progression or unacceptable toxicity.

Or in combination with chemotherapy:

* For non-squamous: Cisplatin or Carboplatin plus pemetrexed \& MPDL3280A - 3 weekly for 4 cycles followed by MPDL3280A and pemetrexed 3 weekly until progression or unacceptable toxicity or completion of a total of 35 cycles. MPDL3280A will then continue 3 weekly until progression or unacceptable toxicity.
* For squamous: Carboplatin plus paclitaxel \& MPDL3280A - 3 weekly for 4 cycles followed by MPDL3280A 3 weekly until progression or unacceptable toxicity.

Trastuzumab emtansine (T-DM1) 3.6mg/kg - 3 weekly until PD IV infusion

Intravenous (IV) infusion, as monotherapy of in combination with chemotherapy

MPDL3280A

Powder for concentrate for solution for infusion

Trastuzumab emtansine

Charles Swanton

DARWIN II is a multi-arm non-randomised phase II trial, Eligible patient will be those who relapse with NSCLC (clinical trials.gov ref. NCT02183883). .

The trial will investigate assess if intra-tumour heterogeneity (clonal vs subclonal actionable mutation) is associated with PFS.

Patients without an actionable mutation will receive MPDL3280A (atezolizumab), a monoclonal antibody targeting anti-PDL1, as monotherapy or in combination with chemotherapy, The options for combination therapy will vary depending on the histology of the NSCLC (i.e. non-squamous or squamous).

Patients with BRAFV600 mutations, HER2 Amplification, ALK/RET gene rearrangements will be enrolled into arms treating with vemurafenib, trastuzumab emtansine and alectinib respectively.

DARWIN II will include extensive exploratory biomarker analysis to investigate a number of genomic and immune markers that may predict response to MPDL3280A (atezolizumab) and help guide future clinical trial design.

DARWIN II is an exploratory phase II study examining the role of intra-tumour heterogeneity and predicted neo-antigens on the anti-tumour activity of anti-PDL1 immunotherapy.

It will examine how clonal dominance and intratumour heterogeneity influence outcomes after treatment, offering a unique opportunity to decipher mechanisms of resistance to immunotherapy with anti-PDL1. These data will help improve future study design by developing greater understanding of patient selection for immunotherapies in patients with NSCLC. The relationship between intratumour heterogeneity and cfDNA/CTCs will also be explored in DARWIN II, which may develop tools for patient selection and monitoring to be examined further in future studies. Results from DARWIN II will help to identify a biomarker for anti-PD-L1 therapy which could be used for patient stratification in future phase III trials of molecules targeting this T-cell inhibitory checkpoint. DARWIN II will also provide preliminary data on efficacy of MPDL3280A, which could be used to design randomised studies.

This is a multicentre non-randomised phase II study based on patients with relapsed NSCLC, who have provided a biopsy sample at the time of relapse.

The study arms:

* Arm 1: Patients without an actionable mutation - MPDL3280A (atezolizumab) monotherapy or in combination with chemptherapy
* Arm 2: BRAFV600 - vemurafenib
* Arm 3: ALK/RET gene rearrangement - alectinib
* Arm 4: HER2 Amplification - trastuzumab emtansine

Arms 2-4 are closed to further recruitment as of 25th May 2021.

Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity

Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity - DARWINII

Defined as the period between the date of registration to the date of subsequent progression or death (whichever occurs first)

Investigator-assessed according to RECISTv1.1 and irRC (Arm 1 only)

Period between first complete response or partial response until the first date recurrence or progressive disease, assessed up to 84 months

Dose reductions, interruptions, modifications and exposure

Interrogation of recurrence and progression biopsies to decipher the molecular basis for resistance in combination with analyses of CTCs/cfDNA as well as CT imaging heterogeneity analyses

Hoffmann-La Roche

University College, London

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Urinary Bladder Neoplasms

Carcinoma, Transitional Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Seagen Trial Information Support

Nataliya Mar

Vadim Koshkin

Laura Graham

Casey Williams

Christian Pfister

Medical Monitor

This study is being done to learn about urothelial cancers that make HER2 and how that affects treatment choices for participants with urothelial cancer. During this study, the medical and health records of participants will be reviewed to learn more about their health.

Participants will have urothelial cancer that has grown in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic).

HER2 and LA/mUC: A Multi-country Chart Review Cohort Study

A Retrospective Chart Review of Real-world Treatment Outcomes in Patients With Locally Advanced Unresectable or Metastatic Urothelial Cancer Based on HER2 Expression

The proportion of participants who have a best overall response (BOR) based on complete response (CR) or partial response (PR). The BOR for each participant is the best response (radiographically documented and measurable disease or physician-assessed response) achieved after the start date of the lines of treatment (LOT) prior to the initiation of any subsequent LOT.

Time from the index date to date of death from any cause.

Agent, reason for change of LOT, surgery, radiotherapy, number of LOT, treatments in each LOT, mean number of LOT, median time to discontinuation of each LOT

The proportion of participants who had a real-world BOR based on CR or PR. The BOR for each participant is the best response (radiographically documented and measurable disease or physician-assessed response) achieved after the start date of the LOT prior to the initiation of any subsequent LOT.

Time from the start date of the LOT to the end date of the same LOT for any reason.

The time from the start date of each LOT to the initiation of the next LOT for any reason.

Time from the index date to the first recorded disease progression (radiographically documented and measurable disease or physician assessed response) or death from any cause, before the start of next LOT whichever occurs first.

The duration of time from the first documented CR or PR in the LOT to the first recorded disease progression (radiographically documented and measurable disease or physician-assessed response) or death from any cause before the start of the next LOT, whichever occurs first.

Seagen Inc.

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Lapatinib

Patients will receive trastuzumab-emtansine, iv 3,6 mg/kg every 21 days. Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever come first

Salvatore Siena, MD

This is a phase II, open label, multicenter study. Patients with advanced colon rectal cancer (CRC) harboring an amplified HER2 that have been previously treated and progressed with an aNti-HER2 treatment, will be treated with the anti HER2 antibody conjugate trastuzumab emtansine (TDM1).

Patients will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death. Main objective of the study is the evaluation of objective response rate according to RECIST 1.1 criteria. Disease control rate, defined as the sum of complete, partial and stable disease patients over total patient, followed by response duration, time to progression and safety are secondary endpoints.

In metastatic colorectal cancer, HER2 amplified patients relapsing after initial long-lasting response to the anti HER combination of trastuzumab + lapatinib, HER2 gene amplification, and the ensuing high levels of HER2 expression on the tumor surface, persist in spite of the tumor progression as determined by HER2 amplified ctDNA levels measured at progression and HER2 IHC findings on rebiopsies of resistant tumors. These findings offer an unexpected 'precision chemotherapy' rescue potential, in spite of progression under anti HER2 treatment and were confirmed experimentally in a HER2 amplified mCRC PDX (metastatic ColoRectal Carcinoma Patient Derived Xenografts), model generated from the viable biopsy of a relapsing HERACLES patient. In this model a randomized trial comparing TDM1 to pertuzumab versus control (6 animal per arm), showed that T-DM1, but not pertuzumab treated animals achieved tumor disappearance. The results of this experiment confirm the principle strength of targeted toxins which is based on their bipartite structure, with one component binding to a disease-specific cell-surface target molecule and the other conferring cytotoxicity, once internalized. In this case HER2 amplification confer to the tumor the characteristics of a 'molecular sponge' for TDM1 with the trastuzumab moiety targeting the still over-abundant HER2 bound to the cell-surface of anti HER2 resistant tumor cell clusters, thus allowing for a 'surgical' delivery of the emtansine cytotoxicity moiety. Given the good predictability of mCRC PDXs model, as testified by HERACLES TRIAL results (NCT03225937), investigators believe that this activity signal should be tested in the clinic. It is therefore proposed a proof-of-concept trial of T-DM1 in HER2 amplified mCRC patients progressing or relapsing after trastuzumab-lapatinib treatment.

Study of Trastuzumab-emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib.

Open-label, Phase II Study of Trastuzumab Emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib: HERACLES RESCUE. (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification - REchallenge With her2 Selective Cytotoxic Uptake of Emtansine)

Fondazione del Piemonte per l'Oncologia

Skin and Connective Tissue Diseases

Stomach Neoplasms

Breast 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.

Pembrolizumab

Disitamab vedotin

Given into the vein (IV; intravenous) every 2 weeks.

disitamab vedotin

Given by IV on Day 1 of each 6-week cycle.

pembrolizumab

Isaac Bowman

Abhishek Tripathi

Alexandra Drakaki

Helen Moon

Amir Harandi

Pareshkumar Patel

Rohit Jain

Barry Berman

Steve McCune

Peter H O'Donnell

Clara Hwang

Elisabeth Heath

Eric Batts, MD

Oscar B Goodman Jr.

Thomas P Bradley

Matthew Galsky

Gopakumar Iyer

Earle Burgess

Jason Robert Brown

Saikrishna Gadde

Matthew T Campbell

Jeanny B Aragon-Ching, MD, F.A.C.P.

Evan Yu

Ariel Nelson

Mirta Varela

Gabriela Gatica

Hernan Cutuli

Juan Pablo Sade

Mark McGregor

Sanjeev Sewak

Niara Oliveira

Laurence Krieger, MD

Aaron R. Hansen

Alison Zhang

Bernhard Eigl

Joel Gingerich

April Rose, MD, PhD

Michel Pavic

Luisa Morales Galindo

Carolina Ibanez

Pamela Salman

Avivit Pe'er

Victoria Neiman

Michal Sarfaty

David Sarid

Nobuaki Matsubara

Masashi Nakayama

Naoya Masumori

Atsunari Kawashima

Masayuki Takahashi

Takeshi Yuasa

Joachim Chan

Danish Mazhar

Robert Jones

Thomas Powles

This study is being done to see if a drug called disitamab vedotin, alone or with pembrolizumab, works to treat HER2 expressing urothelial cancer. It will also test how safe the drug is for participants.

Participants will have cancer that has spread in the body near where it started (locally advanced) and cannot be removed (unresectable) or has spread through the body (metastatic).

It will also study what side effects happen when participants get the drug. A side effect is anything a drug does to your body besides treating the disease.

Cohorts A, B, C, and D will enroll simultaneously. Cohort E will begin enrollment after Cohort D participants have completed the DLT evaluation period.

A Study of Disitamab Vedotin Alone or With Pembrolizumab in Urothelial Cancer That Expresses HER2

A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone or in Combination With Pembrolizumab in Subjects With Locally-Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2

The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1

Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

To be summarized using descriptive statistics.

The proportion of participants with confirmed CR or PR according to RECIST v1.1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Deciphering Antitumour Response and Resistance With INtratumour Heterogeneity	NCT02314481	Non-small Cell ...	MPDL3280A Vemurafenib Alectinib Trastuzumab emt...	18 Years -	University College, London
HER2 and LA/mUC: A Multi-country Chart Review Cohort Study	NCT05902494	Urothelial Carc...		18 Years -	Seagen Inc.
Study of Trastuzumab-emtansine in Patients With HER2-positive Metastatic Colorectal Cancer Progressing After Trastuzumab and Lapatinib.	NCT03418558	Metastatic Colo...	Trastuzumab emt...	18 Years -	Fondazione del Piemonte per l'Oncologia
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.
A Study of Disitamab Vedotin Alone or With Pembrolizumab in Urothelial Cancer That Expresses HER2	NCT04879329	Urothelial Carc...	disitamab vedot... pembrolizumab	18 Years -	Seagen Inc.
ELVN-002 With Trastuzumab +/- Chemotherapy in HER2+ Solid Tumors, Colorectal and Breast Cancer	NCT06328738	HER2-positive B... HER2-positive G... HER2 Positive S... HER2 Amplificat... Colorectal Canc...	ELVN-002 Trastuzumab 5-Fluorouracil Oxaliplatin Capecitabine Eribulin paclitaxel Leucovorin	18 Years -	Enliven Therapeutics
ARX788 in Selected HER2-mutated or HER2-amplified/Overexpressed Solid Tumors (ACE-Pan Tumor-02)	NCT05041972	HER2 Mutation-R... HER2 Amplified ...	ARX788	18 Years -	Ambrx, Inc.
ELVN-002 With Trastuzumab +/- Chemotherapy in HER2+ Solid Tumors, Colorectal and Breast Cancer	NCT06328738	HER2-positive B... HER2-positive G... HER2 Positive S... HER2 Amplificat... Colorectal Canc...	ELVN-002 Trastuzumab 5-Fluorouracil Oxaliplatin Capecitabine Eribulin paclitaxel Leucovorin	18 Years -	Enliven Therapeutics
A Study of Disitamab Vedotin Alone or With Pembrolizumab in Urothelial Cancer That Expresses HER2	NCT04879329	Urothelial Carc...	disitamab vedot... pembrolizumab	18 Years -	Seagen Inc.
ELVN-002 With Trastuzumab +/- Chemotherapy in HER2+ Solid Tumors, Colorectal and Breast Cancer	NCT06328738	HER2-positive B... HER2-positive G... HER2 Positive S... HER2 Amplificat... Colorectal Canc...	ELVN-002 Trastuzumab 5-Fluorouracil Oxaliplatin Capecitabine Eribulin paclitaxel Leucovorin	18 Years -	Enliven Therapeutics

Spots Global Cancer Trial Database for her2 amplification