First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, As a Single Agent in Advanced Solid Tumor Patients and in Combination with Fulvestrant in Patients with Advanced Breast Cancer

Relay Therapeutics

Status and phase: Enrolling; Phase 1

Conditions: Endometrial Cancer; Breast Cancer; Solid Tumor, Adult; Unresectable Solid Tumor; PIK3CA Mutation; Metastatic Breast Cancer; HER2-negative Breast Cancer; Advanced Breast Cancer

Treatments: Drug: RLY-2608; Drug: PF-07220060 100mg; Drug: Ribociclib 600mg; Drug: Ribociclib 400mg; Drug: Fulvestrant; Drug: PF-07220060 300 mg; Drug: Palbociclib 125mg

Study type: Interventional

Funder types: Industry

Identifiers

NCT05216432

RLY-2608-101

Details and patient eligibility

About

This is an open-label, FIH study designed to evaluate the maximum tolerated dose, recommended Phase 2 dose, safety, tolerability, PK, pharmacodynamics, and preliminary antineoplastic activity of RLY-2608, in advanced solid tumor patients with a Phosphatidylinositol-4,5-bisphosphate-3 kinase, catalytic subunit alpha (PIK3CA) mutation in blood and/or tumor per local assessment. The study will evaluate RLY-2608 as a single agent for patients with unresectable or metastatic solid tumors. It will also evaluate RLY-2608 in combination RLY-2608 + fulvestrant and in triple combination RLY-2608 + fulvestrant + CDK4/6 inhibitor (palbociclib or ribociclib) or CDK4 inhibitor (PF-07220060) for patients with HR+ HER2- locally advanced or metastatic breast cancer or endometrial cancer (palbociclib or ribociclib Part 1). The RLY-2608 single agent arm, RLY-2608 + fulvestrant combination arm, and triple combination arms will have 2 parts: a dose escalation (Part 1) and a dose expansion (Part 2).

Enrollment: 890 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria

Patient has ECOG performance status of 0-1

One or more documented primary oncogenic PIK3CA mutation(s) in blood and/or tumor per local assessment

• Other potentially oncogenic PIK3CA mutations may be considered but must be approved by the Sponsor prior to enrollment.

Part 1 - Ability to provide archived tumor tissue or be willing to undergo pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2 - Submit tumor tissue prior to study drug initiation for determination of PIK3CA mutation retrospectively.

Key Inclusion for RLY-2608 Single Agent Arm

• [For Part 1]: Evaluable disease per RECIST v1.1
• [For Part 2]: Measurable disease per RECIST v1.1
• Disease that is refractory to standard therapy, intolerant to standard therapy, or has declined standard therapy.
• Part 1- histologically or cytologically confirmed diagnosis of unresectable or metastatic solid tumor
• Part 2 - Unresectable or metastatic solid tumor with PIK3CA mutation(s) and one of the following tumor types:

Group 1: clear cell ovarian cancer Group 2: head and neck squamous cell carcinoma Group 3: cervical cancer Group 4: other solid tumors, excluding colorectal, clear cell ovarian, head and neck squamous cell, and cervical cancers Group 5: unresectable or metastatic solid tumors with PIK3CA double mutations In addition, the SRC (with Sponsor approval) may choose to open additional group(s) of 20 participants to study the clinical activity, safety, and PK/PD in other specified solid tumor types.

Key Inclusion for Combination Arms

• [For Part 1 and Part 2]: Evaluable disease per RECIST v1.1

• [For Part 1 and Part 2]: Male or female with histologically or cytologically confirmed diagnosis of HR+, HER2- unresectable or metastatic breast cancer that is not amenable to curative therapy. Females may be postmenopausal, premenopausal, or perimenopausal. Premenopausal or perimenopausal females must have a histologically or cytologically confirmed diagnosis of HR+ HER2- advanced or metastatic breast cancer that is not amenable to curative therapy and must have been previously treated with GnRH agonist at least 4 weeks prior to start of study drug

• [For Part 1 and Part 2]: Had previous treatment for breast cancer with:

  1. ≤1 line of chemotherapy in the metastatic setting
  2. ≥1 CDK4/6 inhibitor in either the adjuvant and/or metastatic setting
  3. ≥1 antiestrogen therapy in either adjuvant and/or metastatic setting, including, but not limited to, selective estrogen-receptor degraders (eg, fulvestrant), selective estrogen receptor modulators (eg, tamoxifen), and aromatase inhibitors (AI) (letrozole, anastrozole, exemestane), and
  4. ≥1 PARP inhibitor, if appropriate, if documented germline BRCA1/2 mutation Note: Systemic local, loco-regional, or adjuvant treatment with chemotherapy and PARP inhibitors is not to be included in enumeration or previous treatment

[For RLY-2608 + fulvestrant arm; Part 2, Group 2]: Received prior treatment with a PI3Kα or AKT inhibitor and discontinued the inhibitor due to intolerance and not disease progression, where intolerance is defined as treatment discontinuation due to treatment related AE (eg. hyperglycemia, rash, diarrhea, stomatitis) other than severe hypersensitivity reaction and/or life-threatening reactions, such as anaphylaxis and Stevens-Johnson syndrome.

[For triple combination arms; Part 1 only]: Participants who had previous treatment for breast cancer with PI3Kα or AKT inhibitors will be considered.

[For triple combination arms with ribociclib or palbociclib; Part 1 only]: endometrial cancer may be enrolled.

Key Exclusion Criteria

Prior treatment with PI3Kα, AKT, or mTOR inhibitors (except for RLY-2608 + fulvestrant arm, Part 2, Group 2; and triplet combinations, Part 1).

Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.

History of hypersensitivity to PI3K inhibitors. For combination arms only: hypersensitivity to fulvestrant, palbociclib, ribociclib, and/or PF-07220060, as appropriate for the combination.

Past medical history of or ongoing ILD, or pneumonitis requiring intervention. Participants with past history of resolved Grade 1 pneumonitis may be considered, except in triple combination arms.

Any of the following cardiac criteria:

• Mean resting corrected QT interval (QTc) >470 msec. For triple combination arm with ribociclib: Mean QTcF ≥450 msec.
• Patient has a history of prolonged QT syndrome or torsades de pointes. Patient has a familial history of prolonged QT syndrome.
• Clinically significant, uncontrolled cardiovascular disease

CNS metastases or primary CNS tumor that is associated with progressive neurologic symptoms

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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890 participants in 7 patient groups

RLY-2608 for patients with unresectable or metastatic solid tumors

Experimental group

Description:

Multiple doses of RLY-2608 for oral administration.

Treatment:

Drug: RLY-2608

RLY-2608 + fulvestrant combination for HR+ HER2- locally advanced or metastatic breast cancer

Experimental group

Description:

Oral dose of RLY-2608 in addition to fulvestrant as determined during Part 1 Dose Escalation.

Treatment:

Drug: Fulvestrant

Drug: RLY-2608

RLY-2608+fulvestrant+palbo125mg for HR+HER2 locally advanced/metastatic breast cancer/endometrial ca

Experimental group

Description:

Oral dose of RLY-2608 in addition to fulvestrant and palbociclib 125mg as determined during Part 1 Dose Escalation.

Treatment:

Drug: Palbociclib 125mg

Drug: Fulvestrant

Drug: RLY-2608

RLY-2608+fulvestrant+ribo400mg for HR+HER2 locally advanced/metastatic breast cancer/endometrial ca

Experimental group

Description:

Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 400mg as determined during Part 1 Dose Escalation.

Treatment:

Drug: Ribociclib 400mg

Drug: Fulvestrant

Drug: RLY-2608

RLY-2608+fulvestrant+ribo600mg for HR+HER2 locally advanced/metastatic breast cancer/endometrial ca

Experimental group

Description:

Oral dose of RLY-2608 in addition to fulvestrant and ribociclib 600mg as determined during Part 1 Dose Escalation.

Treatment:

Drug: Fulvestrant

Drug: Ribociclib 600mg

Drug: RLY-2608

RLY-2608+fulvestrant+PF-07220060 100 mg for HR+ HER2- locally advanced or metastatic breast cancer

Experimental group

Description:

Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 100 mg as determined during Part 1 Dose Escalation

Treatment:

Drug: Fulvestrant

Drug: PF-07220060 100mg

Drug: RLY-2608

RLY-2608+fulvestrant+PF-07220060 300 mg for HR+ HER2- locally advanced or metastatic breast cancer

Experimental group

Description:

Oral dose of RLY-2608 in addition to fulvestrant and PF-07220060 300 mg as determined during Part 1 Dose Escalation

Treatment:

Drug: PF-07220060 300 mg

Drug: Fulvestrant

Drug: RLY-2608