(HARMONY) Study of BLU-701 in EGFR-mutant NSCLC

NCT05153408 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: BLU-701-1101
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 7

Brief Summary

This is a Phase 1/2, open-label, first-in-human (FIH) study is designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of BLU-701 as monotherapy or in combination with either osimertinib or platinum-based chemotherapy in patients with EGFRm NSCLC.

Conditions

Lung Neoplasm; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; EGFR C797S; EGFR C797A; EGFR L858R; EGFR Exon 19 Deletion; EGFR Gene Mutation; EGF-R Positive Non-Small Cell Lung Cancer; EGFR Mutation Resulting in Tyrosine Kinase Inhibitor Resistance; EGFR Activating Mutation; Thoracic Neoplasms; Antineoplastic Agents; Protein Kinase Inhibitors; EGFR C797G; EGFR C797X; Non Small Cell Lung Cancer

Keywords

Targeted therapy; EGFR; NSCLC; non-small cell lung cancer; EGFR mutant NSCLC

Outcome Measures

Primary Outcomes (4)

• [Phase 1] Determine the maximum tolerated dose (MTD) of BLU-701 monotherapy, BLU-701 in combination with osimertinib, and BLU-701 in combination with platinum-based chemotherapy

  MTD determination: dose limiting toxicity (DLT) rate

  Up to 12 months

• [Phase 1] Determine the recommended Phase 2 dose (RP2D) of BLU-701 monotherapy, BLU-701 in combination with osimertinib, and BLU-701 in combination with platinum-based chemotherapy

  RP2D determination: DLT, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary safety and antitumor activity data

  Up to 12 months

• [Phase 1] Overall safety profile

  Rate and severity of adverse events

  Up to 12 months

• [Phase 2] Overall response rate (ORR)

  ORR - the proportion of patients who experience a best response of confirmed CR or PR according to RECIST 1.1

  Up to 30 months

Secondary Outcomes (13)

• [Phase 1] Overall response rate (ORR)

  Up to 12 months

• [Phase 1 and Phase 2] Duration of response (DOR)

  Up to 42 months

• [Phase 1 and Phase 2] To characterize the PK profile of BLU-701

  Up to 42 months

• [Phase 1] To assess treatment-induced modulation of EGFR pathway biomarkers for BLU-701 monotherapy

  Up to 42 months

• [Phase 2] Overall safety profile

  Up to 42 months

Study Arms (4)

Part 1A: BLU-701 as monotherapy

EXPERIMENTAL

Phase 1 dose escalation of BLU-701 as monotherapy at various dose levels

Drug: BLU-701

Part 1B: BLU-701 with osimertinib

EXPERIMENTAL

BLU-701 in combination with osimertinib 40 mg or 80 mg tablets for oral administration

Drug: BLU-701; Drug: osimertinib

Part 1C: BLU-701 with platinum-based chemotherapy

EXPERIMENTAL

BLU-701 in combination with platinum-based chemotherapy (carboplatin and pemetrexed): Carboplatin - IV infusion dosed to target AUC of 5-6 mg/mL min q3w Pemetrexed - IV infusion dosed to 500 mg/m2 q3w

Drug: BLU-701; Drug: carboplatin; Drug: pemetrexed

Part 2A: BLU-701 as monotherapy

EXPERIMENTAL

Phase 2 expansion group for BLU-701 as monotherapy at a dose determined during Part 1A in patients harboring the EGFR C797X resistance mutation

Drug: BLU-701

Interventions

BLU-701 DRUG

BLU-701 for oral administration

Part 1A: BLU-701 as monotherapy; Part 1B: BLU-701 with osimertinib; Part 1C: BLU-701 with platinum-based chemotherapy; Part 2A: BLU-701 as monotherapy

osimertinib DRUG

Osimertinib tablets for oral administration

Also known as: Tagrisso

Part 1B: BLU-701 with osimertinib

carboplatin DRUG

IV infusion of carboplatin

Part 1C: BLU-701 with platinum-based chemotherapy

pemetrexed DRUG

IV infusion of pemetrexed

Part 1C: BLU-701 with platinum-based chemotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years of age at the time of signing the informed consent.
• Pathologically confirmed metastatic NSCLC.
• Tumor mutation profile determined locally via next generation sequencing (NGS), using tumor tissue (preferably from a progressing lesion) and/or ctDNA in plasma. For Phase 1, it is preferable that samples used for analysis be obtained during or after disease progression on the last EGFR-targeted TKI received. For Phase 2, samples used for analysis must be obtained during or after disease progression on the last EGFR-targeted TKI received.
• All Parts: activating EGFR mutation (Ex19Del or L858R)
• Part 2A: Tumor must additionally harbor an EGFR C797X resistance mutation.
• Previously received:
• Part 1A and 2A: At least 1 prior third-generation EGFR-targeted TKI, such as osimertinib
• Part 1B: Patients must have experienced progressive disease while on osimertinib, were able to tolerate prior osimertinib 80 mg QD dose, and continuing on osimertinib is deemed to be in the patient's best interests in the opinion of the Investigator.
• Patients who have discontinued osimertinib may be eligible, if no more than 6 weeks elapse between the discontinuation of prior osimertinib and resumption of osimertinib on study.
• Part 1C: At least 1 prior EGFR-targeted TKI
• Willing to provide pretreatment tumor sample (either an archival sample or a sample obtained by pretreatment biopsy. For Phase 1, it is preferable that pretreatment tumor sample be obtained from a progressing lesion and during or after disease progression on the last EGFR-targeted TKI received. For Phase 2, pretreatment tumor sample must be obtained during or after disease progression on the last EGFR-targeted TKI treatment received. Patients without appropriate archival tissue available, where biopsy is not considered safe and/or medically feasible, may be discussed with the study medical monitor and approved for enrollment on a case-by-case basis.
• Part 2A: at least 1 measurable target lesion per RECIST 1.1 as assessed by the Investigator
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Agrees to use contraception consistent with local regulations

You may not qualify if:

• Have disease that is suitable for local therapy administered with curative intent.
• Have tumor that harbors EGFR T790M mutation or any additional known driver alterations (including but not limited to, EGFR exon 20 insertions, or pathologic abnormalities of KRAS, BRAF V600E, NTRK1/2/3, HER2, ALK, ROS1, MET, or RET).
• Have NSCLC with mixed cell histology or a tumor with known histologic transformation (NSCLC to SCLC, SCLC to NSCLC, or epithelial to mesenchymal transition).
• Have received the following anticancer therapy:
• Any third-generation EGFR TKI (such as osimertinib) within 7 days prior to the planned first dose of study drug. Note: patients in Part 1B do not require a wash-out period for osimertinib.
• Part 2A: Previous therapy with first- or second-generation EGFR TKI, such as erlotinib, gefitinib, afatinib or dacomitinib.
• Part 1C: Prior platinum-based chemotherapy for advanced or metastatic disease.
• Any immunotherapy or other antibody therapy (including EGFR-targeted antibodies or bi-specific antibodies) within 21 days prior to the first dose of study drug.
• Any other systemic anticancer therapy within 14 days or 5 half-lives prior to the first dose of study drug, whichever is the shortest, but with a minimum of 7 days in all circumstances. BLU-701 may be started within these washout periods if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
• Radiotherapy to a large field or including a vital organ (including whole brain radiotherapy or stereotactic radiosurgery to brain) within 14 days before the first dose of study drug. Radiotherapy to a focal site of disease that did not include a vital organ (such as a limb) within 7 days before the first dose of study drug.
• Have CNS metastases or spinal cord compression that is associated with progressive neurological symptoms or requires increasing doses of corticosteroids to control the CNS disease. If a patient requires corticosteroids for management of CNS disease, the dose must have been stable for the 2 weeks preceding treatment. Asymptomatic CNS and leptomeningeal disease is allowed and, when measurable, should be captured as target lesions.
• Have any of the following laboratory abnormalities on last laboratory assessment prior to initiation of study drug (i.e., C1D1 or Screening):
• Absolute neutrophil count (ANC) \<1.0×109/L (for patients in Part 1C: \<1.5×109/L)
• Platelet count \<75×109/L (for patients in Part 1C: \<100×109/L)
• Hemoglobin ≤8.0 g/dL (red blood cell transfusion and erythropoietin may be used to reach at least 8.0 g/dL but must have been administered at least 2 weeks prior to the first dose of study drug).

Sponsors & Collaborators

• Blueprint Medicines Corporation: lead

Study Sites (7)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

New York University (NYU) Langone Medical Center

New York, New York, 10016, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

NEXT Virginia

Fairfax, Virginia, 22031, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Thoracic Neoplasms

Interventions

osimertinib; Carboplatin; Pemetrexed

Condition Hierarchy (Ancestors)

Bronchial Diseases; Neoplasms, Glandular and Epithelial

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2021
• First Posted: December 10, 2021
• Study Start: January 13, 2022
• Primary Completion: December 9, 2022
• Study Completion: December 9, 2022
• Last Updated: June 18, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)