Crizotinib in Lobular Breast, Diffuse Gastric and Triple Negative Lobular Breast Cancer or CDH1-mutated Solid Tumours (ROLo)

• ClinicalTrials.gov Identifier: NCT03620643
• Recruitment Status: Recruiting
• First Posted: August 8, 2018
• Last Update Posted: January 6, 2023
• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborators: Pfizer; Breast Cancer Now
• Information provided by (Responsible Party): Royal Marsden NHS Foundation Trust

Study Description

Brief Summary:

The purpose of this study is to find out how effective the combination of crizotinib and fulvestrant is in shrinking lobular breast cancer tumours. The investigators will also be assessing the side effects of the combination of crizotinib tablets and fulvestrant injections. The side effects and the doses of crizotinib and fulvestrant have already been evaluated in large clinical trials, but this is the first time these two drugs will be combined together.

Condition or disease	Intervention/treatment	Phase
Lobular Breast Carcinoma; Gastric Cancer; Triple Negative Breast Cancer; CDH1 Gene Mutation	Drug: Crizotinib Oral Capsule [Xalkori]; Drug: Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex or generic]	Phase 2

Detailed Description:

This clinical study is looking at whether a drug called crizotinib, which is used in some patients with lung cancer, is effective in a sub-type of breast cancer, called lobular breast cancer. As the majority of lobular breast cancers are oestrogen receptor positive (ER+ve), crizotinib will be combined with a second drug, fulvestrant, to try to block tumour growth that is driven by oestrogen.

Crizotinib targets cancers with genetic changes in two genes called ALK and ROS1. Lung cancers with changes in these genes usually get smaller when treated with crizotinib. Laboratory work at the Institute of Cancer Research has shown that lobular breast cancer cells, due to a mutation in a different gene called CDH1, appear to be similarly affected by crizotinib.

Fulvestrant is an oestrogen receptor down regulator and blocks the effects of oestrogen on oestrogen receptor positive (ER+ve) breast cancer cells. Fulvestrant is an established and approved anti-hormone therapy which patients with breast cancers are receiving in the clinic. It is possible that the combination of crizotinib and an anti-oestrogen agent will shrink the tumour(s) more effectively and prevent further growth. Because fulvestrant is only effective in post-menopausal women, if participants have not yet gone through the menopause, participants will need to start (or continue to receive) a monthly injection under the skin to temporarily stop the function of the participants ovaries to be eligible to take part in the trial.

This injection is called goserelin and has to be started at least 4 weeks before the first day of treatment on the trial.

The overall aims of this clinical study are to find out:

• The proportion of patients whose tumour(s) shrink when they are treated with crizotinib and fulvestrant
• The safety and tolerability of fulvestrant in combination with crizotinib, to determine that they can be given together without unacceptable side effects
• What the drugs do to the tumours, which will help us decide which patients may benefit from this combination in the future

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 58 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This multi-centre study design will aim to complete recruitment over 18 months from six high volume centres including the Royal Marsden. Parallel recruitment to breast and basket cancer cohorts will take place for this study.
• Masking: Single (Participant)
• Primary Purpose: Other
• Official Title: Phase II Study of ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer, Diffuse Gastric Cancer, Triple Negative Lobular Breast Cancer or CDH1-mutated Solid Tumours
• Actual Study Start Date: May 9, 2019
• Estimated Primary Completion Date: May 1, 2023
• Estimated Study Completion Date: July 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Crizotinib Oral Capsule [Xalkori] monotherapy; Arm 1 - Gastric cancer cohort (n=29 participants) will be treated with monotherapy called Crizotinib Oral Capsule [Xalkori] (250 mg b.d) taken on a continuous dosing schedule. One treatment cycle for Crizotinib is 28 days long.	Drug: Crizotinib Oral Capsule [Xalkori]; Crizotinib 250 mg Crizotinib 200mg; Other Name: Xalkori
Active Comparator: Crizotinib Oral Capsule [Xalkori] plus Fulvestrant injection; Arm 2 - Lobular Breast Cancer cohort (n=29 participants) will be treated with combination therapy. The combination therapy includes; Crizotinib Oral Capsule [Xalkori] (250mg b.d.) plus Fulvestrant 50 mg/mL Prefilled Syringe [Faslodex or generic] intramuscular (IM) injection (500 mg per 1 cycle (q28 days, plus loading dose on day 15).	Drug: Crizotinib Oral Capsule [Xalkori]; Crizotinib 250 mg Crizotinib 200mg; Other Name: Xalkori; Drug: Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex or generic]; Fulvestrant (Faslodex or generic) is supplied as two 5-mL clear neutral glass (Type 1) barrels, each containing 250mg/5mL of fulvestrant solution for intramuscular injection and fitted with a tamper evident closure.; Other Name: Faslodex

Outcome Measures

Primary Outcome Measures :

1. Percentage of Breast Cancer Cohort Participants With Objective Response Assessed Using RECIST v1.1 [ Time Frame: From Day 1 to Progressive Disease, assessed up to end of study (up to approximately 48 months) ]
   To assess confirmed response rate by RECIST 1.1 of crizotinib and fulvestrant in advanced E-cadherin negative, ER positive lobular breast cancer.
2. Percentage of Basket Cohort Participants With Objective Response Assessed Using RECIST v1.1 [ Time Frame: From Day 1 to Progressive Disease, assessed up to end of study (up to approximately 48 months) ]
   To assess confirmed response rate by RECIST 1.1 of crizotinib monotherapy in advanced E-cadherin negative, diffuse gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid tumour.

Secondary Outcome Measures :

1. Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs) [ Time Frame: From Day 1 to 90 days after last dose of study drug, assessed up to end of study (up to approximately 45 months) ]
   To assess the overall safety and tolerability of crizotinib with fulvestrant in the breast cancer cohort and as monotherapy in the basket cancer cohort. Toxicity will be assessed by CTCAE (version 4) every 4 weeks during study treatment. Adverse events, including serious adverse events, will be recorded until 30 days after the last dose of study treatment with crizotinib.
2. Progression-free survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in both gastric and breast cancer cohorts [ Time Frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (up to approximately 48 months) ]
   PFS is defined as the time from baseline treatment to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (>/=) 20 percent (%) relative increase and >/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
3. Assessment of overall survival in each cohort [ Time Frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (up to approximately 48 months) ]
   Overall survival, calculated from day 1 of study treatment to the date of death from any cause.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

- Patients with histological diagnosis of E-cadherin negative inoperable or metastatic diffuse gastric cancer (basket cohort), Or inoperable or metastatic triple negative lobular breast cancer (basket cohort) Or inoperable or metastatic CDH1-mutated solid tumour with allele fraction ≥20% (basket cohort) Or recurrent inoperable locally advanced ER positive/HER2 negative lobular breast cancer (breast cohort).

Assessment of E-cadherin, ER and HER2 status as per local assessment.

- Lobular breast cancer patients previously treated with at least one prior line of therapy including at least one prior line of hormone therapy for advanced disease, but no more than three prior lines of chemotherapy for advanced disease.

Gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid tumour patients previously treated with at least one prior therapy for advanced disease OR relapsing within one year of completing (neo) adjuvant chemotherapy OR unsuitable for chemotherapy in the opinion of the investigator (for example patient choice not to have chemotherapy, or no suitable chemotherapy agent).

• Measurable disease (RECIST 1.1)
• Haematological and biochemical indices within the ranges shown in protocol. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial.
• Female patients with child-bearing potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial. Both male and female patients of reproductive potential must agree to use two forms of highly effective contraception (see below) for 2 weeks before starting the study treatment, throughout the treatment period and for 90 days after discontinuation of treatment with crizotinib and 2 years after the last dose of fulvestrant.

NOTE: it is only considered highly effective if the patient is refraining from sexual intercourse during the entire period of risk associated with the study treatments

The oral contraceptive pill may be ineffective when taken with crizotinib so is not an acceptable means of contraception for female patients during this study but can be used by female partners of male patients.

• 18 years of age or over with written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up.
• World Health Organisation (WHO) performance status 0,1 or 2
• Estimated life expectancy of at least 3 months in the opinion of the investigator
• Pre-/peri-menopausal ER+ lobular breast cancer patients must be willing to receive gosarelin injections every 28 days.
• Signed and dated informed consent.
• Patients willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other procedures.

Exclusion Criteria:

• Systemic chemotherapy or investigational medicinal products during the previous four weeks, or hormonal therapy within 7 days except luteinizing hormone-releasing hormone (LHRH) analogues for ovarian suppression. Bisphosphonates or RANK ligand antagonists are permitted for the management of bone metastases.
• Previous treatment with any agent that inhibits ROS1
• Mixed ductal/lobular breast cancer, unless both ductal and lobular components are CDH1 negative by local assessment
• Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks or radiation therapy within 14 days prior to study entry
• Patients with known symptomatic brain metastases requiring steroids, untreated brain metastases or spinal cord compression
• Any of the following within 12 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack. Uncontrolled hypertension or cardiac dysrhythmia including atrial fibrillation.
• QT interval, corrected >470 ms or the use of bradycardic agents, drugs which prolong the QT interval and/or anti-arrhythmic agents within 12 days before the first dose of crizotinib or during study treatment.
• Use of drugs that are known potent cytochrome P450 (CYP) 3A4 inhibitors or moderate or strong CYP 3A4 inducers within 12 days before the first dose of crizotinib. Us of CYP3A4 substrates with a narrow therapeutic index (such as ciclosporin) is also not permitted within 12 days prior or during the study treatment.
• Patients on warfarin. Patients requiring anticoagulation for rate-controlled AF or previous venous thromboembolism should be switched to low-molecular weight heparin.
• Known HIV or AIDS-related illness, active infection requiring systemic therapy, or positive HBV or HCV test indicating acute or chronic infection.
• Inability or unwillingness to swallow pills, or (for patients receiving fulvestrant) receive IM injections.
• Other severe acute or chronic medical condition or psychiatric condition, recent or active suicidal ideation or behaviour, or end stage renal disease on haemodialysis, or laboratory abnormality that may increase the risk associated with study participation or investigational products administration or may interfere with the interpretation of results and, in the judgment of the Investigator, would make the patient inappropriate study entry.
• Persisting toxicity related to prior therapy >Grade 1 (except for stable peripheral neuropathy grade ≤2 or alopecia grade ≤2).
• Pregnancy or lactation.
• Diagnosis of other malignancy within 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix, or low-grade (Gleason ≤6) prostate cancer.
• Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this study. Participation in an observational trial would be acceptable.
• Immunocompromised status due to current known active infection with HIV or due to the use of immunosuppressive therapies for other conditions
• Known prior or suspected hypersensitivity to investigational products or to any of the excipients.
• Patients at risk for gastrointestinal perforation (due to e.g., history of diverticulitis).
• Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial.

Contacts and Locations

Contacts

Contact: Rebecca Ruiz; 02078082887; rolo.trial@rmh.nhs.uk

Contact: Alicia Okines; 020 7811 8100; Alicia.Okines@rmh.nhs.uk

Locations

United Kingdom

Beatson West of Scotland Cancer Centre; Recruiting

Glasgow, United Kingdom

Principal Investigator: Dr Iain MacPherson

St Luke's Cancer Centre; Withdrawn

Guildford, United Kingdom

Clatterbridge Cancer Centre; Withdrawn

Liverpool, United Kingdom

Royal Marsden NHS Foundation Trust; Recruiting

London, United Kingdom, SW3 6JJ

Contact: Alicia Okines 020 7811 8100 Alicia.Okines@rmh.nhs.uk

Principal Investigator: Dr Alicia Okines

Guys and St Thomas NHS Foundation Trust; Recruiting

London, United Kingdom

Principal Investigator: Professor Elinor Sawyer

University College London Hospital; Recruiting

London, United Kingdom

Principal Investigator: Dr Rebecca Roylance

The Christie NHS Foundation Trust; Recruiting

Manchester, United Kingdom

Principal Investigator: Dr Anne Armstrong

Sponsors and Collaborators

Royal Marsden NHS Foundation Trust

Pfizer

Breast Cancer Now

Investigators

• Study Chair: Professor Peter Schmid; St Bart's Hospital

More Information

Publications:

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Cristofanilli M, Gonzalez-Angulo A, Sneige N, Kau SW, Broglio K, Theriault RL, Valero V, Buzdar AU, Kuerer H, Buchholz TA, Hortobagyi GN. Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol. 2005 Jan 1;23(1):41-8. doi: 10.1200/JCO.2005.03.111. Erratum In: J Clin Oncol. 2013 Aug 10;31(23):2977. Buccholz, Thomas A [corrected to Buchholz, Thomas A].

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Pernot S, Voron T, Perkins G, Lagorce-Pages C, Berger A, Taieb J. Signet-ring cell carcinoma of the stomach: Impact on prognosis and specific therapeutic challenge. World J Gastroenterol. 2015 Oct 28;21(40):11428-38. doi: 10.3748/wjg.v21.i40.11428.

Peng Z, Li Z, Gao J, Lu M, Gong J, Tang ET, Oliner KS, Hei YJ, Zhou H, Shen L. Tumor MET Expression and Gene Amplification in Chinese Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer. Mol Cancer Ther. 2015 Nov;14(11):2634-41. doi: 10.1158/1535-7163.MCT-15-0108. Epub 2015 Sep 1.

Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010 Feb;10(2):116-29. doi: 10.1038/nrc2780.

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Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, Tye LM, Christensen JG, Wilner KD, Clark JW, Iafrate AJ. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Nov 20;371(21):1963-71. doi: 10.1056/NEJMoa1406766. Epub 2014 Sep 27.

Lennerz JK, Kwak EL, Ackerman A, Michael M, Fox SB, Bergethon K, Lauwers GY, Christensen JG, Wilner KD, Haber DA, Salgia R, Bang YJ, Clark JW, Solomon BJ, Iafrate AJ. MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. J Clin Oncol. 2011 Dec 20;29(36):4803-10. doi: 10.1200/JCO.2011.35.4928. Epub 2011 Oct 31.

Lauren Christine Harshman, K.P.G., Laura Polacek, Mary-Ellen Taplin, Atish Dipankar Choudhury, Mark M Pomerantz, Joaquim Bellmunt, Channing Yu, Zijie Sun, Sandy Srinivas, Philip W. Kantoff, Christopher Sweeney. An investigator-initiated phase I study of crizotinib in combination with enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) before or after progression on docetaxel. in ASCO Annual Meeting. 2016. Chicago: J Clin Oncol.

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Okines A, Irfan T, Asare B, Mohammed K, Osin P, Nerurkar A, Smith IE, Parton M, Ring A, Johnston S, Turner NC. Clinical outcomes in patients with triple negative or HER2 positive lobular breast cancer: a single institution experience. Breast Cancer Res Treat. 2022 Apr;192(3):563-571. doi: 10.1007/s10549-021-06432-z. Epub 2022 Feb 4.

• Responsible Party: Royal Marsden NHS Foundation Trust
• ClinicalTrials.gov Identifier: NCT03620643
• Other Study ID Numbers: CCR4684
• First Posted: August 8, 2018
• Last Update Posted: January 6, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Royal Marsden NHS Foundation Trust:

Advanced E-cadherin negative gastric cancer; Oestrogen receptor positive lobular breast cancer; Crizotinib; Fulvestrant

Additional relevant MeSH terms:

Breast Neoplasms; Stomach Neoplasms; Triple Negative Breast Neoplasms; Carcinoma, Lobular; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Ductal, Lobular, and Medullary; Fulvestrant; Crizotinib; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Estrogen Receptor Antagonists; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action