NCT00721409

Study Of Letrozole With Or Without Palbociclib (PD-0332991) For The First-Line Treatment Of Hormone-Receptor Positive Advanced Breast Cancer

Completed Phase 2 Results posted Last updated 4 November 2019

What this trial tests

Phase 2 trial testing PD 0332991 in Breast Cancer in 177 participants. Completed in 20 December 2017.

Timeline

15 September 2008

Primary endpoint
29 November 2013

20 December 2017

Quick facts

Lead sponsor	Pfizer
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Masking	none
Primary purpose	treatment
Enrollment	177
Start date	15 September 2008
Primary completion	29 November 2013
Estimated completion	20 December 2017
Sites	104 locations across France, Italy, South Africa, Russia, Ukraine, Ireland, Germany, Hungary

Drugs / interventions tested

• PD 0332991
• letrozole — full drug profile →
• letrozole — full drug profile →

Conditions studied

• Breast Cancer — all drugs for Breast Cancer →

Sponsor

Pfizer — full company profile →

Who can join

18 and older, female only, with Breast Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With Treatment-Emergent Adverse Events (TEAEs; All Causalities) at Phase 1 Primary · Maximum treatment duration (approximately 55 months)

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Participants with AEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	12

Participants with SAEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	2

Participants with Grade 3 or 4 AEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	11

Participants with Grade 5 AEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	0

Number of Participants With Treatment-Related Adverse Events at Phase 1 Primary · Maximum treatment duration (approximately 55 months)

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Participants with AEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	12

Participants with SAEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	0

Participants with Grade 3 or 4 AEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	11

Participants with Grade 5 AEs

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	0

Number of Participants With Dose Limiting Toxicities at Phase 1 Primary · Cycle 2 (4 weeks)

Dose limiting toxicity was defined as any of the following TEAEs occurring during the second cycle of treatment and possibly attributable to the combination of letrozole plus Palbociclib: 1. Grade 4 hematologic toxicity (including platelets \<25,000/μL, ANC \<500/μL). 2. Grade 3 neutropenia associated with a documented infection or fever ≥38.5°C. 3. Grade ≥3 non-hematologic toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea, hypertension). 4. Delay by ≥1 week in receiving the next scheduled dose of either study treatment due to persisting treatment-re

Grade 4 Neutropenia

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	2

<80% of doses due to elevated creatinine

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	1

Progression-Free Survival (PFS) at Phase 2 - Investigator Assessment Primary · From randomization date to date of first documentation of progression or death (assessed up to 41 months)

PFS was defined as the time from randomization (or the first dose of study treatment for non-randomized studies) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PFS calculated as (Weeks or Months) = (first event date minus randomization or the first dose date plus 1) divided by 7 (or 30.44 if in months). PFS is usually characterized by the median, 25% percentile,75% percentile and their 95% Confidence Intervals (CIs).

Group	Value	95% CI
Phase 2 (Palbociclib + Letrozole)	20.2	13.8 – 27.5
Phase 2 (Letrozole)	10.2	5.7 – 12.6
Ph2P1 (Palbociclib + Letrozole)	26.1	11.2 – NA
Ph2P1 (Letrozole)	5.7	2.6 – 10.5
Ph2P2 (Palbociclib + Letrozole)	18.1	13.1 – 27.5
Ph2P2 (Letrozole)	11.1	7.1 – 16.4

Objective Response Rate - Percentage of Participants With Confirmed Objective Tumor Response at Phase 1 Secondary · From Baseline up to end of study (assessed up to 55 months)

Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. Per RECIST v1.0: CR defined as disappearance of all target lesions and non-target lesions. PR defined as ≥30% decrease in sum of the longest diameters (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST associated to non-progressiv

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	33.3	9.9 – 65.1

Percentage of Participants With Clinical Benefit Response (CBR) at Phase 1 Secondary · From Baseline up to end of study (assessed up to 55 months)

CBR is defined as a confirmed CR, confirmed PR, or stable disease (SD) for at least 24 weeks on study according to RECIST. Confirmed responses are those that persisted on repeat imaging \>= 4 weeks after initial response.

Group	Value	95% CI
Phase 1 (Palbociclib + Letrozole)	83.3	51.6 – 97.9

Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC24) at Phase 1 Secondary · Cycle 1 Day 14, and Cycle 2 Day 14

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.

Group	Value	95% CI
Palbociclib Alone (Cycle 1 Day 14)	1982	± 29
Palbociclib + Letrozole (Cycle 2 Day 14)	1933	± 31

Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Maximum Observed Plasma Concentration (Cmax) at Phase 1 Secondary · Cycle 1 Day 14, and Cycle 2 Day 14

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.

Group	Value	95% CI
Palbociclib Alone (Cycle 1 Day 14)	115.8	± 28
Palbociclib + Letrozole (Cycle 2 Day 14)	108.4	± 29

Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Time to Maximum Plasma Concentration (Tmax) at Phase 1 Secondary · Cycle 1 Day 14, and Cycle 2 Day 14

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.

Group	Value	95% CI
Palbociclib Alone (Cycle 1 Day 14)	7.92	2.17 – 8.20
Palbociclib + Letrozole (Cycle 2 Day 14)	7.92	2.00 – 8.08

Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Terminal Plasma Half-life (t1/2) at Phase 1 Secondary · Cycle 1 Day 14, and Cycle 2 Day 14

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.

Group	Value	95% CI
Palbociclib Alone (Cycle 1 Day 14)	28.81	2.17 – 8.20
Palbociclib + Letrozole (Cycle 2 Day 14)	NA	2.00 – 8.08

Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Clearance (CL/F) at Phase 1 Secondary · Cycle 1 Day 14, and Cycle 2 Day 14

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.

Group	Value	95% CI
Palbociclib Alone (Cycle 1 Day 14)	63.08	2.17 – 8.20
Palbociclib + Letrozole (Cycle 2 Day 14)	NA	2.00 – 8.08

Summary of Plasma Palbociclib Steady-state Pharmacokinetic Parameter Following Palbociclib Alone and in Combination With Letrozole: Apparent Volume of Distribution (Vz/F) at Phase 1 Secondary · Cycle 1 Day 14, and Cycle 2 Day 14

On Cycle 1 Day 14, plasma pharmacokinetic samples were collected prior to and 1, 2, 4, 8, 12, 24, 48, 96 and 120 hours after Palbociclib dosing. On Cycle 2 Day 14, plasma pharmacokinetic samples for Palbociclib and letrozole were collected prior to and 1, 2, 4, 8, 12 and 24 hours after Palbociclib and letrozole dosing.

Group	Value	95% CI
Palbociclib Alone (Cycle 1 Day 14)	2583	2.17 – 8.20
Palbociclib + Letrozole (Cycle 2 Day 14)	NA	2.00 – 8.08

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up to 28 days after last dose of study drug (for a maximum of 86 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase 1 (Palbociclib + Letrozole)

Serious: 2/12 (17%)

Deaths: 0/12

Phase 2 (Palbociclib + Letrozole)

Serious: 22/83 (27%)

Deaths: 3/83

Phase 2 (Letrozole)

Serious: 6/77 (8%)

Deaths: 1/77

Ph2P1 (Palbociclib + Letrozole)

Serious: 10/33 (30%)

Deaths: 1/33

Ph2P1 (Letrozole)

Serious: 2/29 (7%)

Deaths: 0/29

Ph2P2 (Palbociclib + Letrozole)

Serious: 12/50 (24%)

Deaths: 2/50

Ph2P2 (Letrozole)

Serious: 4/48 (8%)

Deaths: 1/48

Serious adverse events (49 terms)

Reaction	System	Phase 1 (Palbociclib + Let…	Phase 2 (Palbociclib + Let…	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letro…	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letro…	Ph2P2 (Letrozole)
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—
Colitis ischaemic	Gastrointestinal disorders	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—
Gastrointestinal disorder	Gastrointestinal disorders	—	—	—	—	—	—	—
Ileus	Gastrointestinal disorders	—	—	—	—	—	—	—
Oesophageal achalasia	Gastrointestinal disorders	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—	—	—
Disease progression	General disorders	—	—	—	—	—	—	—
Pain	General disorders	—	—	—	—	—	—	—
Erysipelas	Infections and infestations	—	—	—	—	—	—	—
Gangrene	Infections and infestations	—	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—
Staphylococcal bacteraemia	Infections and infestations	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Fractured sacrum	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Hip fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Humerus fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—

Other adverse events (166 terms — click to expand)

Reaction	System	Phase 1 (Palbociclib + Let…	Phase 2 (Palbociclib + Let…	Phase 2 (Letrozole)	Ph2P1 (Palbociclib + Letro…	Ph2P1 (Letrozole)	Ph2P2 (Palbociclib + Letro…	Ph2P2 (Letrozole)
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Leukopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Hot flush	Vascular disorders	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Asthenia	General disorders	—	—	—	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—	—	—	—
Bone pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Neuropathy peripheral	Nervous system disorders	—	—	—	—	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—	—
Mucosal inflammation	General disorders	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Rash	Skin and subcutaneous tissue disorders	—	—	—	—	—	—	—
Toothache	Gastrointestinal disorders	—	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—	—

Most-reported serious reactions: Pulmonary embolism, Back pain, Intervertebral disc protrusion, Anaemia, Cardiac failure, Abdominal pain, Colitis ischaemic, Diarrhoea.

Data from ClinicalTrials.gov NCT00721409 adverse events section.

Sponsor's own description

The study is aimed to confirm that letrozole + PD 0332991 is safe and tolerable and to assess the effect of the combination on advanced breast cancer

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Cell cycle proteins as promising targets in cancer therapy.
   Otto T, Sicinski P. · · 2017 · cited 1412× · PMID 28127048 · DOI 10.1038/nrc.2016.138
2. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.
   Finn RS, Crown JP, Lang I, Boer K, et al · · 2015 · cited 1403× · PMID 25524798 · DOI 10.1016/s1470-2045(14)71159-3
3. Targeting CDK4 and CDK6: From Discovery to Therapy.
   Sherr CJ, Beach D, Shapiro GI. · · 2016 · cited 729× · PMID 26658964 · DOI 10.1158/2159-8290.cd-15-0894
4. Cyclin D1, cancer progression, and opportunities in cancer treatment.
   Qie S, Diehl JA. · · 2016 · cited 527× · PMID 27695879 · DOI 10.1007/s00109-016-1475-3
5. The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer.
   Ding L, Cao J, Lin W, Chen H, et al · · 2020 · cited 385× · PMID 32183020 · DOI 10.3390/ijms21061960
6. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer.
   Ye F, Dewanjee S, Li Y, Jha NK, et al · · 2023 · cited 361× · PMID 37415164 · DOI 10.1186/s12943-023-01805-y
7. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.
   Vora SR, Juric D, Kim N, Mino-Kenudson M, et al · · 2014 · cited 361× · PMID 25002028 · DOI 10.1016/j.ccr.2014.05.020
8. Breast Cancer Treatments: Updates and New Challenges.
   Burguin A, Diorio C, Durocher F. · · 2021 · cited 297× · PMID 34442452 · DOI 10.3390/jpm11080808