Informations générales (source: ClinicalTrials.gov)
First-in-Human Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, as a Single Agent in Patients With Advanced Solid Tumors and in Combination With Endocrine Therapy +/- a CDK4/6 or CDK4 Inhibitor in Patients With Advanced Solid Tumors or Advanced Breast Cancer
Interventional
Phase 1
Relay Therapeutics, Inc. (Voir sur ClinicalTrials)
décembre 2021
avril 2027
02 octobre 2025
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.
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).
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Santiago PONCE-AIX | 17/05/2024 13:42:13 | Contacter | ||
Critères
Tous
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 [Escalation] - Ability to provide archived tumor tissue or be willing to undergo
pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2 [Expansion] -
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: Escalation]: Evaluable disease per RECIST v1.1
- [For Part 2: Expansion]: 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 with other specified solid tumor types.
Key Inclusion for Combination Arms:
- Doublet combination arms [Part 1 and Part 2]: Evaluable disease per RECIST v1.1
- Triplet combination arms:
- [Part 1 and Part 2 Dose Expansion, Group 1]: Evaluable disease per RECIST.
- [Part 2 Dose Expansion, Group 2]: Measurable disease per RECIST. Bone-only lytic or
lytic/blastic disease with at least 1 measurable soft-tissue component per RECIST
may be eligible.
- [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- locally advanced or metastatic
breast cancer that is not amenable to curative therapy and must have initiated
treatment with a gonadotropin-releasing hormone (GnRH) agonist at least 4 weeks
prior to start of study drug with continuation of GnRH agonist for the duration of
study treatment (GnRH agonist recommended for males).
- Had previous treatment for breast cancer with: [Does not apply to triplet
combination arms, Part 2 Dose Expansion, Group 2]:
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 double combination arm; Part 2 Dose Expansion, Group 2]: Received prior treatment
with a PI3Kα, AKT, or mTOR 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 dose escalation]: Participants who had previous
treatment for breast cancer with PI3Kα, AKT, mTOR inhibitors and discontiuned due to
participant/physician decision, intolerance, or disease progression will be considered.
[For triple combination arms, Part 2 Dose Expansion, Group 2]: Participants must be
intolerant to or have declined standard therapy for locally advanced or metastatic
HR+/HER2- PIK3CA-mutated breast cancer. Prior endocrine therapy and CDK4/6inhibitors are
allowed as follows:
1. Participants must have progressed during (neo)adjuvant endocrine therapy or within12
months of completing (neo)adjuvant endocrine therapy with an AI or tamoxifen.
2. If a CDK4/6 inhibitor was included as part of (neo)adjuvant therapy, disease must
have recurred/progressed >12 months after completion of the CDK4/6 inhibitor portion
of (neo)adjuvant therapy
Key Exclusion Criteria
Prior treatment with:
1. PI3Kα, AKT, or mTOR inhibitors (all arms except for doublet RLY-2608 + fulvestrant
arm, Part 2, Group 2; and triplet combinations, Part 1 dose escalation).
2. Immune checkpoint inhibitors.
3. Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2
expansion, Group 2 only:
i. Prior systemic chemotherapy or antibody drug conjugate for locally advanced or
metastatic disease. ii. Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally
advanced or metastatic disease.
iii. Prior treatment with fulvestrant or any selective ER degrader, with the exception of
patients who have received fulvestrant or any selective ER degrader as part of
neoadjuvant therapy only and with treatment duration ≤6 months.
Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma
glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.
History of allergy or hypersensitivity to any components or excipients of PI3K
inhibitors. For combination arms only: allergy or hypersensitivity to any components or
excipients of 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.
The following cardiac criteria:
- Mean resting corrected QT interval (QTc) >460 msec
- For triple combination arm with ribociclib: Mean QTcF ≥450 msec (this is what we
confirmed is shown in the redacted version of the protocol.
CNS metastases or primary CNS tumor that is associated with progressive neurologic
symptoms
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 [Escalation] - Ability to provide archived tumor tissue or be willing to undergo
pretreatment tumor biopsy to assess PIK3CA status retrospectively Part 2 [Expansion] -
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: Escalation]: Evaluable disease per RECIST v1.1
- [For Part 2: Expansion]: 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 with other specified solid tumor types.
Key Inclusion for Combination Arms:
- Doublet combination arms [Part 1 and Part 2]: Evaluable disease per RECIST v1.1
- Triplet combination arms:
- [Part 1 and Part 2 Dose Expansion, Group 1]: Evaluable disease per RECIST.
- [Part 2 Dose Expansion, Group 2]: Measurable disease per RECIST. Bone-only lytic or
lytic/blastic disease with at least 1 measurable soft-tissue component per RECIST
may be eligible.
- [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- locally advanced or metastatic
breast cancer that is not amenable to curative therapy and must have initiated
treatment with a gonadotropin-releasing hormone (GnRH) agonist at least 4 weeks
prior to start of study drug with continuation of GnRH agonist for the duration of
study treatment (GnRH agonist recommended for males).
- Had previous treatment for breast cancer with: [Does not apply to triplet
combination arms, Part 2 Dose Expansion, Group 2]:
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 double combination arm; Part 2 Dose Expansion, Group 2]: Received prior treatment
with a PI3Kα, AKT, or mTOR 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 dose escalation]: Participants who had previous
treatment for breast cancer with PI3Kα, AKT, mTOR inhibitors and discontiuned due to
participant/physician decision, intolerance, or disease progression will be considered.
[For triple combination arms, Part 2 Dose Expansion, Group 2]: Participants must be
intolerant to or have declined standard therapy for locally advanced or metastatic
HR+/HER2- PIK3CA-mutated breast cancer. Prior endocrine therapy and CDK4/6inhibitors are
allowed as follows:
1. Participants must have progressed during (neo)adjuvant endocrine therapy or within12
months of completing (neo)adjuvant endocrine therapy with an AI or tamoxifen.
2. If a CDK4/6 inhibitor was included as part of (neo)adjuvant therapy, disease must
have recurred/progressed >12 months after completion of the CDK4/6 inhibitor portion
of (neo)adjuvant therapy
Key Exclusion Criteria
Prior treatment with:
1. PI3Kα, AKT, or mTOR inhibitors (all arms except for doublet RLY-2608 + fulvestrant
arm, Part 2, Group 2; and triplet combinations, Part 1 dose escalation).
2. Immune checkpoint inhibitors.
3. Triplet combinations RLY-2608 + CDK4 or CDK4/6 inhibitor + fulvestrant, Part 2
expansion, Group 2 only:
i. Prior systemic chemotherapy or antibody drug conjugate for locally advanced or
metastatic disease. ii. Prior CDK2, CDK4, or CDK4/6 inhibitor as treatment for locally
advanced or metastatic disease.
iii. Prior treatment with fulvestrant or any selective ER degrader, with the exception of
patients who have received fulvestrant or any selective ER degrader as part of
neoadjuvant therapy only and with treatment duration ≤6 months.
Type 1 or Type 2 diabetes requiring antihyperglycemic medication, or fasting plasma
glucose ≥140 mg/dL and glycosylated hemoglobin (HbA1c) ≥7.0%.
History of allergy or hypersensitivity to any components or excipients of PI3K
inhibitors. For combination arms only: allergy or hypersensitivity to any components or
excipients of 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.
The following cardiac criteria:
- Mean resting corrected QT interval (QTc) >460 msec
- For triple combination arm with ribociclib: Mean QTcF ≥450 msec (this is what we
confirmed is shown in the redacted version of the protocol.
CNS metastases or primary CNS tumor that is associated with progressive neurologic
symptoms