Palbociclib + Chemotherapy for Solid Tumors

Recruiting at 144 trial locations

Overseen By Pfizer CT.gov Call Center

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Pfizer

Must not be taking: Strong CYP3A inhibitors, Strong UGT1A1 inhibitors

Disqualifiers: Brain tumors, Cardiac disease, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 21

Duration: 12 weeks

128 Participants Needed

Trial Summary

What is the purpose of this trial?

A study to learn about safety and find out maximum tolerable dose of palbociclib given in combination with chemotherapy (temozolomide with irinotecan or topotecan with cyclophosphamide) in children, adolescents and young adults with recurrent or refractory solid tumors (phase 1). Neuroblastoma tumor specific cohort to further evaluate antitumor activity of palbociclib in combination with topotecan and cyclophosphamide in children, adolescents, and young adults with recurrent or refractory neuroblastoma. Phase 2 to learn about the efficacy of palbociclib in combination with irinotecan and temozolomide when compared with irinotecan and temozolomide alone in the treatment of children, adolescents, and young adults with recurrent or refractory Ewing sarcoma (EWS).

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot use strong CYP3A inhibitors or inducers, or strong UGT1A1 inhibitors within 12 days of starting the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug combination Palbociclib + Chemotherapy for Solid Tumors?

Research shows that temozolomide, one of the drugs in the combination, has been effective when used with irinotecan against solid tumors, including malignant glioma. This combination was more effective than using either drug alone, suggesting potential benefits in combining these drugs for treating solid tumors. ^{1 2 3 4 5}

Is the combination of Palbociclib and chemotherapy generally safe for humans?

Temozolomide, when combined with other chemotherapy agents like irinotecan, has shown a good safety profile with manageable toxicities. Irinotecan's main side effects include leukopenia (low white blood cell count) and diarrhea, while temozolomide is known for its broad-spectrum antitumor activity and ability to cross the blood-brain barrier with nonoverlapping toxicities. ^{1 4 6 7 8}

What makes the drug combination of Palbociclib and Chemotherapy unique for treating solid tumors?

This drug combination is unique because it includes Temozolomide, which can cross the blood-brain barrier and is effective in combination therapies due to its broad-spectrum antitumor activity and good safety profile. Additionally, the combination of Temozolomide with Irinotecan has shown enhanced effectiveness against solid tumors, offering a novel approach compared to using these drugs individually. ^{1 2 3 5 8}

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility Criteria

This trial is for children and young adults aged 2-21 with relapsed or refractory solid tumors, including specific types like Ewing sarcoma. They must have a certain level of physical ability, adequate organ function, measurable disease, and not be pregnant. Those with severe allergies to the drugs used or serious health issues are excluded.

Inclusion Criteria

My cancer has returned or didn't respond to treatment, as confirmed by a lab test.

My kidney function, measured by creatinine levels, is within the normal range.

My liver is working well.

Exclusion Criteria

Prior intolerability to specified treatments

I haven't taken strong CYP3A affecting drugs recently.

Severe acute or chronic medical or laboratory abnormalities

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Phase 1: Participants receive palbociclib in combination with chemotherapy (temozolomide with irinotecan or topotecan with cyclophosphamide) to determine the maximum tolerable dose. Phase 2: Participants receive palbociclib in combination with irinotecan and temozolomide or irinotecan and temozolomide alone for efficacy evaluation.

12 weeks

Multiple visits per cycle (each cycle is 21 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and laboratory abnormalities.

At least 28 days after last dose

Long-term Follow-up

Participants are monitored for overall survival and progression-free survival.

Up to 2 years

Treatment Details

Interventions

• Cyclophosphamide
• Irinotecan
• Palbociclib
• Temozolomide
• Topotecan

Trial Overview The study tests Palbociclib combined with chemotherapy (Temozolomide/Irinotecan or Topotecan/Cyclophosphamide) to find the safest high dose in phase 1 and its effectiveness compared to just chemo in phase 2 for Ewing sarcoma.

Participant Groups

Group I: Phase 2 Arm A Experimental Treatment 3 Interventions

Palbociclib in combination with irinotecan and temozolomide.

Group II: Phase 1 Tumor specific cohort - Neuroblastoma Experimental Treatment 3 Interventions

Palbociclib in combination with topotecan and cyclophosphamide.

Group III: Phase 1 Experimental Treatment 5 Interventions

Palbociclib in combination with temozolomide and irinotecan and/or with topotecan and cyclophosphamide.

Group IV: Phase 2 Arm B Active Control 2 Interventions

Irinotecan and temozolomide alone.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Children's Oncology Group

Collaborator

Trials

467

Recruited

241,000+

Children's Oncology Group (COG)

Collaborator

Trials

3

Recruited

380+

Findings from Research

Temozolomide is a promising drug for combination therapies due to its ability to cross the blood-brain barrier, good safety profile, and effectiveness against solid tumors like malignant glioma, especially when combined with carmustine or irinotecan.

Studies indicate that administering carmustine before temozolomide results in lower toxicity and a higher maximum tolerated dose, while the combination of temozolomide followed by irinotecan shows greater effectiveness than either drug alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. Prados, M.[2019]

The TMZ-resistant glioma cell line SF188/TR showed a 6-fold resistance to temozolomide and cross-resistance to various other anticancer agents, indicating a significant challenge in treating resistant tumors.

Increased activity of the enzyme alkylguanine alkyltransferase (AGT) was identified as a primary mechanism of resistance to TMZ, while changes in the balance of pro-apoptotic and anti-apoptotic proteins contributed to broader cross-resistance to other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. Ma, J., Murphy, M., O'Dwyer, PJ., et al.[2022]

In a study of 117 patients with clear cell carcinoma of the ovary, the combination of irinotecan hydrochloride and cisplatin (CPT-P) showed a progression-free survival (PFS) rate of 55% at 5 years, suggesting it may be an effective treatment option.

While the CPT-P regimen did not show a statistically significant survival advantage over the standard paclitaxel and carboplatin (TC) treatment, it demonstrated comparable efficacy, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progression-free survival and overall survival of patients with clear cell carcinoma of the ovary treated with paclitaxel-carboplatin or irinotecan-cisplatin: retrospective analysis. Takano, M., Sugiyama, T., Yaegashi, N., et al.[2018]

In a study involving 107 patients with recurrent malignant glioma, the maximum tolerated dose (MTD) of irinotecan (CPT-11) was found to be 325 mg/m² for those taking enzyme-inducing anticonvulsants and 125 mg/m² for those not taking them, indicating significant variability in tolerance based on concurrent medications.

The combination of CPT-11 and temozolomide (TMZ) resulted in a 14% radiographic response rate, with patients showing a median time to disease progression of 54.9 weeks, suggesting that this treatment regimen may be effective for recurrent glioblastoma multiforme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. Reardon, DA., Quinn, JA., Rich, JN., et al.[2022]

Irinotecan, a derivative of camptothecin, has shown significant activity against recurrent malignant glioma in clinical trials, confirming its potential as a treatment option for this aggressive brain tumor.

Combining irinotecan with alkylating agents like BCNU or temozolomide enhances its antitumor effects, leading to ongoing Phase II trials to evaluate these combinations in adults with malignant glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. Friedman, HS., Keir, ST., Houghton, PJ.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Temozolomide in combination with other cytotoxic agents. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Biochemical changes associated with a multidrug-resistant phenotype of a human glioma cell line with temozolomide-acquired resistance. [2022]

3. Japan pubmed.ncbi.nlm.nih.gov

Progression-free survival and overall survival of patients with clear cell carcinoma of the ovary treated with paclitaxel-carboplatin or irinotecan-cisplatin: retrospective analysis. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Phase I trial of irinotecan plus temozolomide in adults with recurrent malignant glioma. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Temozolomide: a novel oral alkylating agent. [2018]

6. Japan pubmed.ncbi.nlm.nih.gov

[Topoisomerase inhibitors developing in Japan]. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Effective conversion of irinotecan to SN-38 after intratumoral drug delivery to an intracranial murine glioma model in vivo. Laboratory investigation. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

The emerging role of irinotecan (CPT-11) in the treatment of malignant glioma in brain tumors. [2018]