Capivasertib + Palbociclib + Fulvestrant for HR+/HER2- Advanced Breast Cancer (CAPItello-292).

• Sponsor: AstraZeneca (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04862663
• Collaborator: (none)
• Enrollment: 700
• Locations: 65
• Arms: 2
• Anticipated Duration (Months): 75.8
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Phase Ib/III Randomised Study of Capivasertib plus Palbociclib and Fulvestrant versus Placebo plus Palbociclib and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer (CAPItello-292).

Condition or Disease	Intervention/Treatment	Phase
Locally Advanced (Inoperable) or Metastatic Breast Cancer	Drug: Capivasertib; Drug: Matched Capivasertib Placebo; Drug: Fulvestrant; Drug: Palbociclib	Phase 3

Detailed Description

This Phase Ib/III study (CAPItello-292) aims to evaluate the efficacy, safety and the degree of added benefit of capivasertib combined with palbociclib and fulvestrant in participants with endocrine-resistant locally advanced (inoperable) or metastatic HR+/HER2- breast cancer. Although the dosing regimens of capivasertib + fulvestrant and of palbociclib + fulvestrant are established, the dose and schedule for the triplet combination (capivasertib + palbociclib + fulvestrant) needs to be confirmed. Therefore, the initial dose finding Phase Ib part of the study will confirm the recommended Phase III doses (RP3D) and schedule of administration of capivasertib and palbociclib for the triplet combination including fulvestrant which will then be used in the Phase III part of this study.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 700 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase Ib: Open, Parallel groups allowed, recruiting approx. 72 participants. Phase III: Randomised, double blind, recruiting approx. 628 participants.Phase Ib: Open, Parallel groups allowed, recruiting approx. 72 participants. Phase III: Randomised, double blind, recruiting approx. 628 participants.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase Ib/III Randomised Study of Capivasertib Plus Palbociclib and Fulvestrant Versus Placebo Plus Palbociclib and Fulvestrant in Hormone Receptor-Positive and Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced, Unresectable or Metastatic Breast Cancer
• Actual Study Start Date: May 10, 2021
• Anticipated Primary Completion Date: Jun 9, 2025
• Anticipated Study Completion Date: Sep 3, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Capivasertib Plus Palbociclib and Fulvestrant Capivasertib Plus Palbociclib and Fulvestrant	Drug: Capivasertib; Phase Ib: Capivasertib 320 mg, administered PO BD 4 days on /3 days off per week for 4 weeks (28 days cycle) Phase III: : Capivasertib, administered PO BD 4 days on / 3 days off per week for 4 weeks (28 days cycle) at the dose confirmed in the phase Ib portion; Drug: Fulvestrant; Phase Ib and Phase III: 500 mg (2 injections of 250 mg) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter; Drug: Palbociclib; Phase Ib: Potential range 75 mg, 100 mg, 125 mg. Once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete 28-day cycle Phase III: Administrated once daily for 21 days of 28-day cycle), at the dose confirmed in the phase 1b portion
Placebo Comparator: Placebo Plus Palbociclib and Fulvestrant Placebo Plus Palbociclib and Fulvestrant	Drug: Matched Capivasertib Placebo; Phase Ib: Not applicable Phase III: Administrated BD 4 days on 3 days off/week for 4 weeks, at the dose confirmed in the phase Ib portion; Drug: Fulvestrant; Phase Ib and Phase III: 500 mg (2 injections of 250 mg) on Day 1 of Weeks 1 and 3 of Cycle 1, and then on Day 1, Week 1 of each cycle thereafter; Drug: Palbociclib; Phase Ib: Potential range 75 mg, 100 mg, 125 mg. Once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete 28-day cycle Phase III: Administrated once daily for 21 days of 28-day cycle), at the dose confirmed in the phase 1b portion

Outcome Measures

Primary Outcome Measures

1. Phase Ib: 1. The number of participants with dose-limiting toxicity, as defined in the protocol. [Within the first 28 day cycle.]

   Dose-limiting toxicity as described in the protocol that is not related to disease progression, intercurrent illness or concomitant medications and that, despite optimal therapeutic intervention, meets protocol-defined criteria.

2. Phase Ib: 2. The number of participants with treatment-related adverse events. [From baseline up to approximately 24 months.]

   Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of participants with treatment-related adverse events.

3. Phase Ib: 3. The number of participants with treatment-related serious adverse events. [From baseline up to approximately 24 months.]

   Data will include clinical observations, ECG parameters, clinical chemistry and haematology and vital signs assessed as the number of participants with treatment-related adverse events.

4. Phase III: 1. Progression Free Survival (PFS). [Up to approximately 33 months.]

   Progression Free Survival (PFS) is defined as time from randomization until progression per RECIST v1.1. as assessed by the investigator or death due to any cause.

Secondary Outcome Measures

1. Phase Ib: 1. PK parameters for palbociclib: Cmax. [Cycle 0 (Cycle 0 is 3 days), Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 1 is 28 days).]

   Maximum observed plasma (peak) drug concentration.

2. Phase Ib: 2. PK parameters for palbociclib: AUC0-72h. [Cycle 0 (Cycle 0 is 3 days).]

   Partial area under the plasma concentration-time curve from zero to 72 hours post-dose.

3. Phase Ib: 3. PK parameters for palbociclib: AUC0-24h. [Cycle 0 (Cycle 0 is 3 days), Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 1 is 28 days).]

   Partial area under the plasma concentration-time curve from zero to 24 hours post-dose.

4. Phase Ib: 4. PK parameters for palbociclib: Cmin. [Cycle 1 Day 11 and Cycle 1 Day 14 (Cycle 0 is 3 days and Cycle 1 is 28 days).]

   Minimum observed plasma drug concentration.

5. Phase Ib: 5. PK parameters for capivasertib: Cmax. [Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days).]

   Maximum observed plasma (peak) drug concentration.

6. Phase Ib: 6. PK parameters for capivasertib: AUC0-12h. [Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days).]

   Partial area under the plasma concentration-time curve from zero to 12 hours post-dose.

7. Phase Ib: 7. PK parameters for capivasertib: Cmin. [Cycle 1 Day 11 (Cycle 0 is 3 days and Cycle 1 is 28 days).]

   Minimum observed plasma drug concentration.

8. Phase Ib: 8. Objective Response Rate (ORR). [Up to approximately 24 months.]

   Objective Response Rate (ORR) is defined as the proportion of patients with measurable disease at baseline who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by the investigator at local site per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

9. Phase Ib: 9. Clinical Benefit Rate (CBR) at 24 weeks. [Up to approximately 24 months.]

   Clinical Benefit Rate (CBR) 24 weeks is defined as the percentage of patients who have a CR or PR or who have SD per RECIST v1.1 as assessed by the investigator at local site for at least 23 weeks after date of first dose.

10. Phase Ib: 10. Duration of Response (DoR). [Up to approximately 24 months.]

    Duration of Response (DoR) will be defined as the time from the date of first documented confirmed response until date of documented progression per RECIST v1.1 as assessed by the investigator at local site or death due to any cause.

11. Phase Ib: 11. Progression Free Survival (PFS). [Up to approximately 24 months.]

    Progression Free Survival (PFS) is defined as time from date of first dose until progression per RECIST v1.1. as assessed by the investigator at local site or death due to any cause.

12. Phase III: 1. Overall Survival (OS). [Up to approximately 60 months.]

    Overall Survival (OS) - time from randomisation until the date of death due to any cause.

13. Phase III: 2. Progression Free Survival (PFS) in PIK3CA/ AKT1/ PTEN-altered population. [Up to approximately 33 months.]

    Progression Free Survival (PFS) - time from randomisation until progression per RECIST v 1.1 as assessed by the PI or death due to any cause.

14. Phase III: 3. Progression Free Survival 2 (PFS2). [Up to approximately 60 months.]

    Progression Free Survival (PFS2) - time from randomisation to the earliest of the progression event, subsequent to first therapy or death.

15. Phase III: 4. Objective Response Rate (ORR). [Up to approximately 33 months.]

    Objective Response Rate (ORR) - the proportion of patients who have a complete or partial response.

16. Phase III: 5. Duration of Response (DoR). [Up to approximately 33 months.]

    Duration of Response (DoR) - the time from the date of first documented response until the date of progression or death.

17. Phase III: 6. Clinical Benefit Rate (CBR) at 24 weeks. [Up to approximately 33 months.]

    Clinical Benefit Rate (CBR) at 24 weeks-the % of patients who have a CR or PR or who have SD for at least 23 weeks after randomization.

18. Phase III: 7. EORTC QLQ-30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items). [Up to approximately 60 months.]

    5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, and nausea/vomiting), and global health status/QoL scale, along with 5 individual item symptom scores (appetite loss, dyspnoea, insomnia, constipation, and diarrhoea. The EORTC QLQ-C30 will be scored according to the EORTC QLQ-C30 Scoring Manual (Fayers et al. 2001). Higher scores on the global measure of health status and functional scales indicate better health status/function, but higher scores on symptom scales/scores represent greater symptom severity.

19. Phase III: 8. 1.EORTC QLQ BR45 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer specific module). [Up to approximately 60 months.]

    The self-administered instrument includes 23-items and yields 5 multi-item scores (body image, sexual functioning, arm symptoms, breast symptoms, and systemic therapy side effects). Additional items yield two multi-item scales: a target symptom scale with three subscales (endocrine therapy, endocrine sexual and skin/mucosa) and a satisfaction scale. In addition, 3 single items are included that assess sexual enjoyment, future perspective and being upset by hair loss. Items are scored on a 4-point verbal rating scale: "Not at All," "A Little," "Quite a Bit," and "Very Much". Scores are transformed to a 0 to 100 scale, where higher scores indicate better functioning, better HRQoL, or greater level of symptoms.

20. Phase III: 9. Time to definitive deterioration of the ECOG (Eastern Cooperative Oncology Group) performance status. [Up to approximately 60 months.]

    Time from randomisation to the earlier of the date of the first definitive deterioration or death due to any cause. Deterioration is defined as a 1-point decrease in ECOG score from baseline.

21. Phase III: 10. Plasma concentration of capivasertib pre- and post-dose. [Up to approximately 60 months.]

    Plasma concentration of capivasertib pre-, and post-dose.

22. Phase III: 11. The number of participants with adverse events. [Up to approximately 60 months.]

    Data will include clinical observations, ECG parameters, clinical chemistry / haematology / glucose metabolism parameters and vital signs assessed as the number of participants with adverse events.

23. Phase III: 12. The number of participants with serious adverse events. [Up to approximately 60 months.]

    Data will include clinical observations, ECG parameters, clinical chemistry / haematology / glucose metabolism parameters and vital signs assessed as the number of participants with serious adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key inclusion criteria for both phases:

1. Adult females (pre- and/or post-menopausal), and adult males.

2. Histologically confirmed HR+/ HER2- breast cancer determined from the most recent tumour sample (primary or metastatic) per the American Society of Clinical Oncology and College of American Pathologists guideline. To fulfil the requirement of HR+ disease, a breast cancer must express ER with or without co-expression of progesterone receptor.

3. Eligible for palbociclib and fulvestrant therapy as per investigator assessment. Previous tolerance to specific CDK4/6 inhibitors and dose levels required.

4. Adequate organ and bone marrow functions.

5. Consent to provide a mandatory FFPE tumour sample.

Inclusion criteria only for phase III:

1. Previous treatment with an ET (tamoxifen or an AI) as a single agent or in combination, with:

2. radiological evidence of breast cancer recurrence or progression while on, or within 12 months of, completing a (neo)adjuvant ET regimen OR

3. radiological evidence of progression while receiving the ET for locally advanced or metastatic breast cancer (this does not need to be the most recent therapy)

4. Received up to a maximum of 1 lines of prior chemotherapy in the advanced setting.

Key exclusion criteria for both phases:

1. History of another primary malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence.

2. Radiotherapy with a wide field of radiation within 4 weeks prior to study treatment initiation and/or radiotherapy with a limited field of radiation for palliation within 2 weeks prior to study treatment initiation. Patients who received prior radiotherapy to ≥25% of bone marrow are not eligible independent of when it was received.

3. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.

4. Persistent toxicities (CTCAE Grade >1) caused by previous anticancer therapy, excluding alopecia. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the AstraZeneca study physician.

5. Spinal cord compression, brain metastases or leptomeningeal metastases unless asymptomatic, treated and stable and not requiring steroids within 4 weeks prior to study treatment initiation.

6. Any of the following cardiac criteria at screening:

7. . Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 consecutive ECGs

8. . Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (eg, complete left bundle branch block, third-degree heart block)

9. . Any factors that increase the risk of QTc prolongation or risk of arrhythmic events

10. . Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure New York Heart Association (NYHA) grade ≥ 2

11. . Uncontrolled hypotension

12. . Cardiac ejection fraction outside institutional range of normal or < 50% (whichever is higher)

13. Any of these clinically significant abnormalities of glucose metabolism at screening:

14. . diabetes mellitus type I or type II requiring insulin treatment

15. . HbA1c ≥ 8.0% (63.9 mmol/mol)

16. Previous allogeneic bone marrow transplant or solid organ transplant.

Key exclusion criteria for the phase III only:

1. Any prior treatment with SERDs, AKT, PI3K or mTOR inhibitors.

2. Prior treatment with CDK4/6 inhibitors in the metastatic setting (prior CDK4/6 inhibitors permitted in the adjuvant setting).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States	90048
2	Research Site	San Francisco	California	United States	94158
3	Research Site	Aurora	Colorado	United States	80045
4	Research Site	Nashville	Tennessee	United States	37203
5	Research Site	San Antonio	Texas	United States	78229
6	Research Site	Darlinghurst		Australia	2010
7	Research Site	Miranda		Australia	2228
8	Research Site	Nedlands		Australia	6009
9	Research Site	Perth		Australia	6009
10	Research Site	Wahroonga		Australia	2076
11	Research Site	Leuven		Belgium	3000
12	Research Site	Chicoutimi		Canada	G7H 5H6
13	Research Site	Montreal		Canada	H3T 1E2
14	Research Site	Beijing		China	100039
15	Research Site	Beijing		China	100044
16	Research Site	Beijing		China	100210
17	Research Site	Beijing		China
18	Research Site	Changchun		China	130000
19	Research Site	Changsha		China	410013
20	Research Site	Chengdu		China	610041
21	Research Site	Guangzhou		China	510060
22	Research Site	Guangzhou		China	510080
23	Research Site	Hangzhou		China	31000
24	Research Site	Hangzhou		China	310016
25	Research Site	Hangzhou		China	310022
26	Research Site	Jinan		China	250001
27	Research Site	Nanchang		China	330006
28	Research Site	Nanchang		China	330009
29	Research Site	Nanjing		China	210029
30	Research Site	Shandong		China
31	Research Site	Shanghai		China	200032
32	Research Site	Shenyang		China	110001
33	Research Site	Shenyang		China	110016
34	Research Site	Urumqi		China	830000
35	Research Site	Wuhan		China	430060
36	Research Site	Xi'an		China	710061
37	Research Site	Xian		China	710100
38	Research Site	Zhengzhou		China	450008
39	Research Site	Odense C		Denmark	5000
40	Research Site	St Herblain		France	44805
41	Research Site	Villejuif		France	94805
42	Research Site	Pondicherry		India	605006
43	Research Site	Koto-ku		Japan	135-8550
44	Research Site	Bydgoszcz		Poland	85-796
45	Research Site	Kraków		Poland	31-501
46	Research Site	Lublin		Poland	20-090
47	Research Site	Warszawa		Poland	02-781
48	Research Site	Warszawa		Poland	02-781
49	Research Site	Barcelona		Spain	08035
50	Research Site	Granada		Spain	18014
51	Research Site	Lérida		Spain	25198
52	Research Site	Madrid		Spain	28040
53	Research Site	Madrid		Spain	28046
54	Research Site	Málaga		Spain	29010
55	Research Site	Pamplona		Spain	31008
56	Research Site	Solna		Sweden	17176
57	Research Site	Bangkok		Thailand	10210
58	Research Site	Bangkok		Thailand	10330
59	Research Site	Bangkok		Thailand	10400
60	Research Site	Bangkok		Thailand	10700
61	Research Site	Chiang Mai		Thailand	50200
62	Research Site	Dusit		Thailand	10300
63	Research Site	Hat Yai		Thailand	90110
64	Research Site	Khon Kaen		Thailand	40002
65	Research Site	Ratchathewi		Thailand	10400

Sponsors and Collaborators

• AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BreastCancerStudyLocator.com

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04862663
• Other Study ID Numbers: D361DC00001
• First Posted: Apr 28, 2021
• Last Update Posted: Aug 1, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Locally advanced (inoperable) or Metastatic Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Fulvestrant; Palbociclib

Study Results

No Results Posted as of Aug 1, 2022