Trial of Palbociclib in Second Line of Advanced Sarcomas With CDK4 Overexpression.

Phase II Multicenter Trial of Palbociclib in Second Line of Advanced Sarcomas With CDK4 Overexpression.

Non-randomized, open, two-cohort, phase II, multicenter national clinical trial. 20 sites in Spain.

Cohort 1 includes soft-tissue sarcoma and osteosarcoma (21 patients), while Cohort 2 includes chordoma patients only (19 patients).

Palbociclib will be administered orally at a dose of 125 mg once a day for 21 consecutive days followed by 7 rest days to comprise a complete cycle of 28 days. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

The main goal is to determine progression-free survival rate (PFSR) according to RECIST 1.1 at 6 months.

Inclusion Criteria (Cohort 1: STS and osteosarcoma):

1. Over-expression of CDK4 (mRNA expression) and a low-to-normal p16 expression (mRNA expression) measured in paraffin embedded tumor samples at study entry.

2. ECOG 0-1 at enrollment.

3. Diagnosis of soft tissue sarcoma or osteosarcoma (in both cases with metastasis or locally advanced, unresectable).

4. Disease progression documented within 6 months prior to study entry.

5. Patients must have the following laboratory results:

   • ANC ≥ 1,500/mm3 (1.5 x 109/L);
   • Platelets ≥ 100,000/mm3 (100 x 109/L);
   • Hemoglobin ≥ 9 g/dL (90 g/L);
   • Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min;
   • Total serum bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if Gilbert's disease);
   • AST and/or ALT ≤ 3 x ULN (≤ 5.0 x ULN if liver metastases present);
   • Alkaline phosphatase ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or hepatic metastasis present);

6. Patients must have signed written informed consent to participate in the clinical study, and to provide at least two paraffin embedded tumor blocks for the molecular analyses at screening stage.

7. Biopsy at baseline if there are no archived tumor samples obtained within 3 months prior to treatment initiation.

8. Patients must have received standard treatments for at least one, two or three lines for advanced disease.

9. Age between 18 and 80 years (both ages included).

10. Measurable disease according to RECIST 1.1 criteria.

11. All patients (men and women) in fertile age must use an effective contraception method during the entire treatment with palbociclib and for at least 90 days after the last dose. Pregnancy must be ruled out through urine or blood test (negative pregnancy test) for the inclusion in the study. Men must be informed to consider spermatic preservation before treatment initiation due to infertility risks.

Exclusion Criteria (Cohort 1: STS and osteosarcoma):

1. Previous treatment with any anti CDK4 or immune checkpoint inhibitor.
2. Diagnosis of Ewing sarcoma or rhabdomyosarcoma.
3. Diagnosis of well differentiated/dedifferentiated liposarcoma.
4. Patients irradiated on the only target lesion available.
5. Patients having received more than three lines for advanced disease.
6. History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
7. Serious cardiovascular disease (NYHA >= 2)
8. Grade 3 or superior toxicity according to CTCAE 4.0 if the investigator considers this can significantly interfere in the toxicity of the drug under study.
9. Patients not recovered from a previous toxicity to at least CTCAE Grade 1 due to prior chemotherapy, radioactive, or biological cancer therapy (including monoclonal antibodies).
10. Patients not recovered from minor or major surgery or having undergone a major surgery within the last 4 weeks prior to initiation of study treatment.
11. Central nervous system metastasis.
12. Pregnant or breastfeeding patients, or those expecting to conceive or father children within the projected duration of treatment.
13. Foods or drugs known as CYP3A4 inhibitors/inducers; CYP3A4 substrates with narrow therapeutic windows, or known to prolong QTc interval.
14. Major surgery, chemotherapy, radiotherapy, any agent under investigation, or other antineoplastic therapy within 4 weeks prior to inclusion. Patients having received a previous radiotherapy ≥25% of bone marrow are not eligible, regardless of when it was received.
15. QTc > 480 ms; personal or family history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsades de Pointes (TdP).
16. Any of the following situations within 6 months prior to study drug administration: myocardial infarction, serious/unstable angina, current cardiac dysrhythmias Grade ≥ 2 NCI-CTCAE version 4.0, atrial fibrillation of any grade, bypass graft in coronary/peripheral artery, symptomatic congestive cardiac failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism.
17. Known hypersensitivity to any PD 0332991 or excipients.
18. Active or recent suicide attempt or behavior.

Inclusion Criteria (Cohort 2: Chordomas):

1. Mutation of CDKN2A gen.

2. ECOG 0-1 at the time of inclusion.

3. Centrally confirmed diagnosis of chordoma (metastatic or locally advanced inoperable).

4. Disease progression according to RECIST 1.1, within the year prior to inclusion, to previous treatment (surgery, radiotherapy or systemic treatment).

5. Patients are not candidates for salvage surgery or radiotherapy at the time of inclusion.

6. Patients must have the following lab results:

   • Absolute neutrophil count ≥ 1,500/mm3 (1.5 x 109/L);
   • Platelets ≥ 100,000/mm3 (100 x 109/L);
   • Hemoglobin ≥ 9 g/dL (90 g/L);
   • Blood creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 60 mL/min;
   • Total blood bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN if Gilbert's disease);
   • AST and/or ALT ≤ 3 x ULN (≤ 5.0 x ULN if there is liver metastasis);
   • Alkaline phosphatase ≤ 2.5 x ULN (≤ 5.0 x ULN if there is bone or liver metastasis);

7. The patients must have signed the written consent to participate in the clinical study, and to provide the tumor blocks in paraffin for the molecular analysis of the screening phase.

8. Biopsy at baseline if there are no archive tumor samples obtained in the 3 months prior to starting treatment. If there are tumor samples within this period, there should not be subsequent treatments.

9. Patients may have received up to 3 previous lines of systemic treatment.

10. Age between 18 and 80 years (both ages included).

11. Measurable disease according to RECIST 1.1 criteria.

12. All patients (male and female) of childbearing potential must use effective contraception throughout treatment with palbociclib and for at least 90 days after the last dose. Pregnancy must be ruled out by urine or blood test (negative pregnancy test) for inclusion in the study. Men should be told to consider sperm preservation before starting treatment due to the risks of infertility.

Exclusion Criteria (Cohort 2: Chordomas):

1. Prior treatment with any anti-CDK4 or immune checkpoint inhibitors.
2. Diagnosis other than chordoma according to central review.
3. Patients irradiated in the only available target lesion.
4. Patients who have received more than three lines for advanced disease.
5. History of other neoplastic disease with the exception of adequately treated basal cell carcinoma or cervical cancer in situ. This criterion will be individually assessed with the research team.
6. Severe cardiovascular disease (NYHA >= 2).
7. Grade 3 toxicity or higher according to CTCAE 5.0 if, in the investigator's opinion, it can significantly interfere with the toxicity of the drug under study.
8. Patients who have not recovered from previous toxicity up to CTCAE grade 1 due to previous antineoplastic treatment with chemotherapy, radiotherapy, or biological therapy (including monoclonal antibodies).
9. Patients who have not recovered from minor or major surgery or who have had major surgery within 4 weeks prior to the start of study treatment.
10. Metastases in the central nervous system.
11. Patients who are pregnant or lactating, or who expect to conceive children during the treatment period.
12. Foods or drugs known to be inhibitors/inducers of CYP3A4; CYP3A4 substrates with narrow therapeutic windows, or known to prolong the QTc interval.
13. Major surgery, chemotherapy, radiation therapy, any investigational agent, or other antineoplastic therapy within 4 weeks prior to enrollment. Patients who have received prior radiation therapy to ≥25% of the bone marrow are not eligible, regardless of when received.
14. QTc > 480 ms; personal or family history of long or short QT syndrome, Brugada syndrome, or known history of QTc prolongation, or Torsades de Pointes (TdP).
15. Any of the following within 6 months prior to study drug administration: Myocardial infarction, severe/unstable angina, current NCI-CTCAE version 5.0 Grade ≥ 2 cardiac dysrhythmias, any grade atrial fibrillation, implant coronary/peripheral artery pacemaker, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, symptomatic pulmonary embolism, or interstitial lung disease (ILD).
16. Known hypersensitivity to any PD 0332991 or excipients.
17. Active or recent suicidal intent or behavior.