A Phase 1, Multicenter, Open-label, Dose Exploration and Dose Expansion Study Evaluating the Safety, Tolerability, Pharmacokinetics and Efficacy of AMG 994 Monotherapy and Combination of AMG 994 and AMG 404 in Subjects With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- AMG 994
- Conditions
- Advanced Solid Tumors
- Sponsor
- Amgen
- Enrollment
- 11
- Locations
- 17
- Primary Endpoint
- Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The primary objective of this study is to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/maximum tolerated combination dose (MTCD) or recommended phase 2 dose (RP2D) of AMG 994 as monotherapy and AMG 994 in combination with AMG 404 in participants with advanced solid tumors.
Detailed Description
AMG 994 will be administered by short term intravenous (IV) infusion once weekly in each 28-day cycle and AMG 404 will be administered by short-term IV infusion once every 4 weeks (Q4W) in a 28 day cycle (on day 1 of cycle 2 and beyond). The study will be conducted in 2 parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures.
- •Age ≥ 18 years at the time of signing informed consent.
- •Life expectancy of \> 3 months, in the opinion of the investigator.
- •Participant must have histologically or cytologically proven metastatic or locally advanced solid tumors of known MSLN expression who have relapsed after and/or are refractory to established and available therapies with known clinical benefit, for which:
- •No standard systemic therapy exists; or
- •Standard systemic therapy has failed or is not available.
- •Dose Expansion (Part 2): Participant must have one of the following malignancies: mesothelioma, pancreatic adenocarcinoma, MSLN positive NSCLC squamous cell carcinoma or adenocarcinoma, high grade serous ovarian carcinoma.
- •At least 1 measurable or evaluable lesion as defined by modified RECIST 1.1 guidelines.
- •Participants must be willing to undergo a biopsy prior to enrollment and during treatment with AMG
- •Participants with treated brain metastases are eligible provided they meet the following criteria:
Exclusion Criteria
- •Disease Related
- •Primary brain tumor, untreated or symptomatic brain metastases and leptomeningeal disease.
- •Other Medical Conditions
- •History of other malignancy within the past 2 years, with the following exception\[s\]:
- •Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician.
- •Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
- •Adequately treated cervical carcinoma in situ without evidence of disease.
- •Adequately treated breast ductal carcinoma in situ without evidence of disease.
- •Prostatic intraepithelial neoplasia without evidence of prostate cancer.
- •Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.
Arms & Interventions
Part 1a: Dose Exploration
Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.
Intervention: AMG 994
Part 1a: Dose Exploration
Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.
Intervention: AMG 404
Part 1b: Dose Exploration
Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.
Intervention: AMG 994
Part 1b: Dose Exploration
Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.
Intervention: AMG 404
Part 2: Dose Expansion
Participants will be administered with the MTD or RP2D of AMG 994 identified in the dose escalation part of the study, in combination with AMG 404.
Intervention: AMG 994
Part 1c: Dose Exploration
Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.
Intervention: AMG 994
Part 1c: Dose Exploration
Determine the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D) of AMG 994, in combination with AMG 404.
Intervention: AMG 404
Part 2: Dose Expansion
Participants will be administered with the MTD or RP2D of AMG 994 identified in the dose escalation part of the study, in combination with AMG 404.
Intervention: AMG 404
Outcomes
Primary Outcomes
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
Time Frame: Up to Day 28 of Cycle 1 (one cycle = 28 days)
DLTs were defined as: * Grade 5 events * Grade 4 neutropenia/thrombocytopenia of any duration * Grade 3 thrombocytopenia w/ clin significant bleeding or lasting \>7 days * Febrile neutropenia * Grade 4 anemia * Grade 3/4 non-hematologic toxicity, except: Grade 3 nausea/vomiting or diarrhea \< 72 hours; Grade 3 fatigue \< 1 week; Asymptomatic grade 3 electrolyte abnormalities that last \< 72 hours, are not clinically complicated, and resolve spontaneously or respond to conventional medical interventions; Grade 3 amylase/ lipase elevations; Other laboratory parameters of grade 3, not considered clinically relevant and improved to grade ≤ 2 within 72 hours. * Any grade 3 event requiring hospitalization * Recurrent grade 2 pneumonitis * Delay in cycle 2 treatment for \> 14 days due to an adverse event in the dose escalation portion of the study * Any event requiring discontinuation of AMG 994
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
Time Frame: From first dose of investigational product through 140 days after last dose (AMG 994 or AMG 404, whichever is later), or end of study (whichever is first); median (min, max) duration was 12.5 ( 1.48, 19.32) months.
TEAEs were those that occurred after the first intervention dose. A serious adverse event (SAE) included outcomes such as death, life-threatening situations, hospitalization or an extended hospital stay, significant incapacity, congenital defects, or other crucial medical events. AE severity followed the CTCAE Version 5.0 scale: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), and grade 5 (death). Clinically significant laboratory results or other assessments (e.g., ECGs, scans, vital signs) that worsened from baseline and were deemed important by the investigator, independent of disease progression, were also considered.
Secondary Outcomes
- Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1(Up to approximately 19.32 months)
- Duration of Response (DoR) Per Modified RECIST 1.1(Up to approximately 19.32 months)
- Overall Survival (OS) Per Modified RECIST 1.1(Up to approximately 19.32 months)
- Progression-free Survival Per Modified RECIST 1.1(Up to approximately 19.32 months)
- Time to Progression (TTP) Per Modified RECIST 1.1(Up to approximately 19.32 months)
- Time to Subsequent Therapy(Up to approximately 19.32 months)
- Maximum Serum Concentration (Cmax) of AMG 994(Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose))
- Time to Maximum Serum Concentration (Tmax) of AMG 994(Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose))
- Minimum Observed Serum Concentration (Cmin) of AMG 994(Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose))
- Cmax of AMG 404(Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose))
- Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994(Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose))
- Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994(Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose))
- Terminal Half-life (t1/2) of AMG 994(Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose))
- Tmax of AMG 404(Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose))
- Cmin of AMG 404(Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose))
- AUCtau of AMG 404(Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose))
- AUClast of AMG 404(Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose))
- T1/2 of AMG 404(Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose))