MEGALiT: A MolEcularly Guided Anti-Cancer Drug Off-Label Trial

Sponsor

Uppsala University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04185831

Collaborator

(none)

154

Enrollment

Locations

Arms

25.4

Anticipated Duration (Months)

51.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective, open-label, non-randomized combined basket- and umbrella trial divided in two parts; a limited feasibility-oriented part 1 including 154 patients and 3 treatment cohorts and part 2 that will include an expanded cohort of patients and treatment cohorts. The overall aims of the study are to test the feasibility, safety and efficacy of comprehensive genomic profiling on fresh tumor biopsies as a basis for treatment decision making and to compare two different sequencing, bioinformatics and decision-making platforms (part 1). Also to evaluate the efficacy and safety of off-label treatment with cancer drugs in patients selected based on genomic biomarker matching.

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor	Drug: Atezolizumab Drug: Everolimus Drug: Cobimetinib	Phase 2

Detailed Description

This is a prospective, open-label, non-randomized combined basket- and umbrella trial divided in two parts; a limited feasibility-oriented part 1 including 154 patients and 3 treatment cohorts (mutation/drug) and part 2 that will include an expanded cohort of patients and treatment cohorts. The overall aims of the study are to test the feasibility, safety and efficacy of comprehensive genomic profiling on fresh tumor biopsies as a basis for treatment decision making and to compare two different sequencing, bioinformatics and decision-making platforms (part 1). Also to evaluate the efficacy and safety of off-label treatment with cancer drugs in patients selected based on genomic biomarker matching.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

154 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Combined umbrella and basket trial. Treatment selection based on mutation status.Combined umbrella and basket trial. Treatment selection based on mutation status.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

MEGALiT - a Multicenter, Basket and Umbrella Explorative Trial on the Efficacy and Safety of Molecular Profile Selected Commercially Available Targeted Anti-cancer Drugs in Patients With Advanced Cancers Progressive on Standard Therapy

Actual Study Start Date :

Oct 20, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NF1/MAP2K1 Cobimetinib, 60mg po daily. 28 day cycle; day 1-21 60mg daily, day 22-28 rest period.	Drug: Cobimetinib MEK inhibitor Other Names: Cotellic
Experimental: MTOR/TSC1/TSC2 Everolimus, 10mg po daily.	Drug: Everolimus MTOR inhibitor Other Names: Afinitor
Experimental: Mutation burden Atezolizumab. 1200mg iv every 3 weeks.	Drug: Atezolizumab PD-L1 inhibitor Other Names: Tecentriq

Arm

Intervention/Treatment

Experimental: NF1/MAP2K1

Cobimetinib, 60mg po daily. 28 day cycle; day 1-21 60mg daily, day 22-28 rest period.

Drug: Cobimetinib

MEK inhibitor

Other Names:

Cotellic

Experimental: MTOR/TSC1/TSC2

Everolimus, 10mg po daily.

Drug: Everolimus

MTOR inhibitor

Other Names:

Afinitor

Experimental: Mutation burden

Atezolizumab. 1200mg iv every 3 weeks.

Drug: Atezolizumab

PD-L1 inhibitor

Other Names:

Tecentriq

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) and tumor control rate [Time Frame: From first dose up to 24 months] [1 year follow-up after LPFV]
The proportion of patients that have a best overall response of complete response (CR), partial response (PR) or stable disease ≥16 weeks, as assessed by RECIST 1.1 criteria

Secondary Outcome Measures

Additional measurements of treatment efficacy [1 year follow-up after LPFV]
Time to and duration of tumor response and stable disease, progression free survival, overall survival and progression free survival on study drug compared with that on the treatment preceding study drug treatment.
Drug-related safety, evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [1 year follow-up after LPFV]
Incidence and severity of study drug related adverse events (AEs) and serious adverse events (SAEs). Include recording of changes in laboratory values, vital signs (body temperature, blood pressure, heart rate, respiratory rate), and assessment of physical, dermatological examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
Biopsy safety: NCI Common Terminology Criteria for Adverse Events 4.03 as grade 3 - 4 adverse event related to the procedure [1 year follow-up after LPFV]
Safety of core needle biopsy in advanced cancer scored according to NCI Common Terminology Criteria for Adverse Events 4.03 as grade 3 - 4 adverse event related to the procedure.
Genomic analysis [1 year follow-up after LPFV]
Actionable target concordance between genomic analysis results from the Foundation Medicine platform F1CDx with that from the similar local analysis.
Overall survival [1 year follow-up after LPFV]
Overall survival of patients starting treatment in accordance with 1 of the 4 groups of genomic markers compared with patients included in the trial but that do not start such treatment due to lack of appropriate marker.
Feasibility of study design [1 year follow-up after LPFV]
Feasibility of comprehensive genomic testing of fresh tumor tissue for treatment decision, defined as the proportion of patients included with actionable genomic analysis within 4 weeks from inclusion

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult (age >18 years)
Patients with histologically-proven, locally advanced or metastatic solid tumor (part 1; hematological malignancies also eligible in part 2) progressive while on last line established therapy considered available for the patient. For re-recruitment (part 2) patients must be progressive while on trial defined treatment or off-protocol treatment.
Fresh tumor sampling by biopsy must be possible, except for patients with CNS malignancy who can be included based on molecular analysis of archived tumor material.
ECOG performance status 0-2.
Patients must have acceptable organ function as defined below:
Absolute neutrophil count ≥ 1.5 x 10^9/L
Hemoglobin > 90 g/L
Platelets > 75 x 10^9/L
Total bilirubin < 2 x ULN
ASAT (SGOT) and ALAT (SGPT) < 2.5 x institutional ULN (or < 5 x ULN in patients with known hepatic metastases)
Serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine clearance ≥ 50 mL/min/1.73 m2
Patients must have objectively measurable disease (by physical or radiographic examination).
Ability to understand and the willingness to sign a written informed consent document.
For orally administered drugs, the patient must be able to swallow and tolerate oral medication and must have no known malabsorption syndrome.
Negative pregnancy test in women of childbearing potential (premenopausal or <12 months of amenorrhea post-menopause and who have not undergone surgical sterilization). Women of childbearing potential must use highly effective method of contraception, i.e. combined hormonal contraception, or progestogen-only hormonal contraception, or intrauterine device, or intrauterine hormone-releasing system, or bilateral tubal occlusion, or vasectomized partner, or sexual abstinence for the duration of participation in the study, and four months following completion of study therapy.
Selected tumor types might have disease-specific inclusion criteria, defined by disease-specific study appendix.

Exclusion Criteria:

Ongoing treatment-related toxicity > grade 2.
Patients receiving any other anti-cancer therapy (cytotoxic, biologic, radiation, or hormonal other than for replacement) except for medications that are prescribed for supportive care but may potentially have an anti-cancer effect (e.g., megestrol acetate, bisphosphonates, somatostatin analogues and prednisone, or equivalent, >5 mg/d). These medications must have been started ≥ 1 week prior to the screening visit on this study. Radiotherapy to non-target lesions is allowed.
Patients pregnant or nursing.
Patients of childbearing potential and sexually active and not willing to use highly effective contraceptive.
Patients with known active progressive CNS metastases. Patients with previously treated CNS metastases are eligible, provided that the patient has not experienced a seizure or had a clinically significant change in neurological status within the 3 months prior to inclusion. All patients with previously treated CNS metastases must be stable for at least 1 month after completion of treatment and off steroid treatment prior to inclusion.
Some concomitant diseases qualified for exclusion as detailed in main protocol.
Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the patient to participate in the trial.